T1- Energy

Among 6 nutrients, only macronutrients (carbs, protein, fat) can provide energy
RNI (Recommended Nutrient Intake)
1. Nutrients:
o A component in food that an organism uses to survive & grow
o Amount required is affected by:
 Age
 Sex
 Physiological condition
o Hence, it’s imp for us to know RNI at dif age group
2. Who come out with RNI?
o Technical Sub-Committee (1969)
 Representative from different background
 IMR
 PHT of MOH
 WHO
 University of Malaya
o Obj: provide advice on dietary aspects of the proposed Applied Nutrition Pilot Project
o 1st meeting: 20/9/2002
o Outcome: RNI book published in 2005
o They need to review & revise RNI from time to time due to
 Advances in scientific knowledge
 Deteriorating state of health of the nation
3. Definition of RNI
o Daily intake which meets the nutrient requirements of almost all apparently healthy individuals in an
age- & sex-specific population group
4. how they come out with ideal body height & weight?
o Calculate average value from healthy population done by local researchers
5. Usage of RNI
o Policy maker
 Plan and monitor national related activity
 Campaign
 New policy
o Program planner
 Health promotion activity
o Food industry & marketing
o Clinical practitioner
 dietitians
o Researcher
Energy Requirement
6. Affected by:
1. Genders
a. Women < men
i. Men more lean body mass
ii.
2. Growth
a. Infant, children vs adults, elderly
3. Age
a. Lower in adulthood
i. Hormones influence appetite, body weight, metabolism change with age
ii. Hence young ppl
4. Physical activity
a. Various activities are clustered accrd to the typical intensity of a day’s effort
b. Physical activity factor for various levels of intensity
5. Body composition
a. Tall > short
i. Larger surface area
b. More hairy
i. More basal metabolism
c. Hence, Asian < western
i. They taller and more hairy than Asian ppl
ii. Hence Malaysia come out with their own set of RNI not using RDA, cause body composition is
different
Method calculating basal energy need:


Direct method= calculate the energy lost as heat from body
Indirect = oxygen consumption
o Metabolic process not only produce heat, but also consume oxygen
Regulation of Food Intake
1. Physiological aspects 色香味+口感
o
o
o
o
Sensation (mouthfeel)
Appearance
Texture (soft, hard, crispy)
Smell (olfaction) & gustation (taste)
 Some chemical can be taste at lower conc than others
 We can compare with the relative taste indices
 Higher indices  lower conc to be detected able to provide more intense taste.

o
o
o
Reference compound  index=1
 The higher the index, the sweeter/ sourer
Fructose is sweeter than sucrose
Citric acid is less sour than HCl
2. Psychological aspects
o
Causes to make healthy food choice
i. Knowledge
1. Level of education
a. Dietitian > business students ..
b. Nutrition savvy
ii. Motivational factors
1. Conducive to proper food choice
a. Intrinsic factors
i. Belief abt health & nutrition
ii. Cognitions (thoughts)  positive
iii. Goal setting, action plants
iv. Self-monitoring & management
v. contracting
b. Extrinsic factors
i. Praise
ii. External Reward
1. Give you iphone if you follow healthy diet
iii. Support frm others
iv. Food available (proper/improper)
v. Physical activity
vi. Models of proper behaviors
2. Conflicting with proper food choice
a. Time:
i. travel
1. Impossible to eat healthily as we wanna try out all the tasty
food within short periods of the time
b. Job, association
c. Characteristic of the regimen/plan
i. Cost
ii. Complexity
d. Personal, family, cultural practices
e. Social occasion
i. Friend
ii. Parties
iii. Celebration
iii. Affective influence (**Feelings & attitudes)
1. Emotional states
a. Boredom
b. Fear, anxiety
c. Depression
d. Happiness
e. Stress
f. weather
2. Physical condition
a. Threat to health
b. Fatigued or rested
c. State of health
d. Severity of illness
Types and Food Sources: Nutritional Interest
 Energy-yielding nutrients
o
Nutrients that break down to yield energy the body can use
o
3 ORGANIC NUTRIENTS: (contain “c” in the structures)
 Carbs
 Fat
 Protein
o Inorganic nutrients:
 Water
 mineral
 Macronutrients  CFP
o
Body needs in relatively large amount (no need yield energy)
 Grams/ day
 Water
o
o
o
Consider macronutrients in this course
But unlike CFP  can’t provide energy
Hence some article or books may not put water under macronutrients
 Calories:
o
o
o
o
o
o
Energy released from CFP  Calories
 Measured in kilocalories
 1 kcal = 1000 cal
 1 kcal = the amt of heat necessary to increase the temp of 1 kg of water 1C
Carbs = 4kcal/g
Protein= 4kcal/g
Fat= 9kcal/g
Alcohol (not a nutrient) =7kcal/g
 Will interfere the body growth and metabolism
All the CPF  acetyl CoA  enter TCA cycle
o
 Micronutrients  vitamins & minerals

Body requires in small amounts
o Mg/ microgram per day

Vitamin vs minerals：
o
o
Similarity:
 Micronutrients
 Non-energy yielding nutrients
DIFFERENCE:
 Vitamin is organic, mineral is inorganic
Carbohydrate:
 Types:
I.
Simple carbs
a. Monosaccharides:
i. All contain same chemical formula C6H12O6 with dif chemical structure (arrangement)
ii. Glucose, fructose, galactose
b. Disaccharides
i. Mono  condensation  disaccharide
ii. Types:
1. Maltose
2. Sucrose= table sugar
3. Lactose= milk sugar
II.
Complex Carbs
a. Oligosaccharides
i. 3-10 sugar units
ii. Eg:
1. Raffinose
2. Stachyose
3. Verbascose
iii. Found mostly in beans, peas, whole grains
iv. Human digestive enzyme X hydrolyze them  prebiotic
b. Polysaccharide:
i. More than 10 units of monosac linked
ii. Types:
1. Glycogen
a. X be found in plant-based food
b. Little in meat
c. Almost X be found in food  food isn’t a significant source of glycogen
2. Starch
a. Amylopectin
i. branched
b. Amylose
i. unbranched
3. Fiber
 Digestion and Absorption of Carbohydrates




 Ultimate goal: glucose absorption & use
In mouth:
 Salivary amylase
 Hydrolyze starch to shorter polysaccharides  maltose
 At neutral pH
 Very little carbs digestion take place here
Stomach:
 Bolus mixed with stomach acid & protein digesting enzymes
 Acid inactivates salivary amylase
 Fibers  delay gastric emptying
 Satiety & fullness
SI: (most carbs digest at proximal SI)
 Starches:
 Pancreatic amylase
I.
Breakdown starch at 1-4 linkages to shorter glucose chains & maltose
 Brush border of enterocyte enzymes
I.
Break disaccharide & oligosaccharide  mono
o Maltase
o Sucrase
o Lactase
Broken monosac  absorbed into bloodstream via capillaries of villi  portal vein to liver




 Fibers:
 Hydrogen positioned on the beta side of the oxygen  enzyme X break the bond
(sterospecificity of enzymes)
LI (focus on fibers)
 Fibers
  attract water  softens stools for passage wo straining
 GI bac ferment some fibers
I.
Generate water, gas, SCFA
 Consumption of large amt of lactose (esp lactase deficiency), fructose, stachyose, raffinose, alcohol
sugars
 Unabsorbed in SI  pass to colon
 Increase gas and loose stools
Absorption:
 Active transport:
 When glucose & galactose at low luminal conc
 involve specific receptors SGLT1 (sodium dependent-glucose/galactose cotransporter)
 need Na+ to facilitate the process
I.
the glucose/galactose binding site is available only when the transport protein bound a
Na+
 ** this is why sodium-glucose drink are used to rehydrate diarrhea or athletes lost too much
fluid
 Facilitated diffusion:
 High luminal conc all monosac use GLUT 2 (Na-independent)
I.
Esp after large carb meal  increase intestinal glucose conc
II.
Facilitated transporter GLUT2
 Fructose
I.
Specific facilitative transporter = GLUT5
II.
Relative slow absorption than glucose & galactose (actively absorbed)
o Can result in a smaller increment of blood glucose
 Fructose is better than glucose/galactose
 Hence fruits sugar is better than other sugar
Metabolism
 Primary: in liver
 Non-insulin dependent
 All sugar  carried directly first to liver
 Fructose & galactose  can be converted into glucose derivatives  same fate as glucose=
I.
stored as liver glycogen
II.
circulate in blood  control BGlvl
III.
catabolize for energy accd to liver energy demand
IV.
if sugar intake exceed body oxidative & storage capacity convert into fat
 little/ no galactose & fructose found in blood
 * Fructose:
I.
Only liver has the receptors for fructose  only liver can use fructose to produce energy
o High-fructose diet  increase risk of fatty liver
 Secondary: muscle & adipose tissue
 Insulin-dependent
 Metabolism & Utilization of Carbohydrates



Glucose is key player (fuel for all cells)
Metabolic pathways:
 Glycogenesis: synthesis of glycogen
 Glycogenolysis: breakdown of glycogen
 Glycolysis: oxidation of glucose  ATP
 Gluconeogenesis: production of glucose frm non-carb intermediates
I.
Lactate, pyruvate, glycerol, certain Amino acid
Hormone:
 Insulin= anabolism , store CFP
 Glucagon= catabolism

1. Storing glucose as glycogen

Liver storage (1/3 of total body glycogen)
 Condensation into glycogen
I.
Eat  BG rise  insulin increase and process glucose  condense into glycogen stored
in liver
 Hydrolysis for release of glucose when needed
I.
Imp during hunger  immediately breakdown int glucose for utility

II.
Directly Release glucose into blood  Imp in maintaining blood glucose homeostasis
III.
But only provide 5% of the energy?
Muscle storage: (2/3 of total body glycogen)
 Cannot directly contribute to blood glucose lvl
I.
It only provides energy within the muscle cells during muscle contraction - X released
into blood
II.
Bcs it lacks the enzyme that converts phosphorylated glucose back to free glucose
 Selfish  only breakdown during exercise
 Although the conc of glycogen in liver is higher than muscle, muscle stores most of the glycogen
(~75%) as muscle make up a much greater portion of the body’s weight
 Storage depends on PA of individual
I.
Can increase glycogen concentration in muscle by increasing physical training
2. Glucose for energy



Glycolysis
 1Glucose  2pyruvate (3carbon compounds)
 Aerobic pathway:
I.
Pyruvate  enter mitochondria  TCA cycle/ Krebs cycle  complete oxidized into
H2O + CO2 + large amt of energy
 Anaerobic:
I.
Pyruvate lactate + small amt energy
o The extra lactate  leave muscle cell  liver  convert into glucose
(gluconeogenesis)
II.
Happens due to lack of O2 / high cellular metabolism
o High intensity exercise
III.
** the major metabolic pathway for RBC as they X have mitochondria
Fuels most of body’s cells
 Esp: brain, nerve cells, RBC only use glucose as fuel
Cellular breakdown of glucose
3. Making glucose from protein





Body would make glucose from other source of nutrients when we lack of glucose
Gluconeogenesis
 Synthesis of glucose from noncarb precursor
I.
Amino acid
II.
glycerol
III.
Lactate
 Primary site:
I.
Liver (most)
II.
Kidney
Body proteins source: liver & skeletal muscles
Reverse the glycolytic pathway
 Consume ATP
 Synthesize glucose
It has to be regulated! Or else too many ammonia and urea produced  affect kidney function
4. Ketone bodies from fat fragments

** only during starvation
 You don’t eat anything (not only not enough glucose like the gluconeogenesis)
I.
Fat (breakdown) ketone body  provide energy
Ketone body may accumulate in our blood if more that our body required 
lead to ketosis  interfere acid-base balance  not good for our body
How to prevent this ketosis?
I.
Daily intake of >= 50-100g carbs for protein sparing (preserve protein) & prevention of
ketosis
o Body prefer glycogen > protein > fat
o



Starvation metabolism changes step:
i. Most of this glucose can be synthesized through gluconeogenesis from glycerol, lactate, and
selected amino acids during the early phase of starvation.
ii. as the starvation continues, the body attempts to protect its protein component and the
amino acid substrates for gluconeogenesis become less available.
iii. This, coupled with the rising ketone level (ketones can cross the blood–brain barrier), serves
to induce the utilization of the ketones by the brain as a metabolic fuel.
iv. after 48 h of starvation, Proteolysis is suppressed by rising levels of growth hormone as the
body attempts to conserve its body proteins. The initial proteolysis, however, serves to
provide the needed amino acids for the synthesis of enzymes needed for survival (enzymes
needed for energy mobilization and conservation). Once these mechanisms are established,
body protein is conserved.
5. Using glucose to make fat

If glycogen capacity is full in liver & muscle
 Extra glucose  fat as storage
 Glucose Homeostasis



Glucose  supply steadily in blood stream
 Source: intestine & liver (secondary: kidney during starvation may gluconeogenesis)
Cond:
 Low BG dizzy & weak
 High BG  fatigue
Regulating hormone:
 Insulin
 Glucagon
I.
Bring glucose out from storage



3. The storage capacity of muscle and liver for glycogen is full, hence insulin may also stimulate
glucose convert into fat
I.
Hence don’t consume more than our RNI for carbs as it will be stored as fat.
Failure in blood glucose regulation
 Diabetes
 hypoglycemia
 diabetes

=chronic disorder of carbs metabolism, usually resulting from insufficient / ineffective insulin
I.

o Clinical: use fasting BG to confirm diabetic status of ppl (repeated fasting BG)
T1DM
I.
Cause: pancreas failed to produce enough insulin
o Mainly due to genetics
II.
Tend to develop at young age
III.
Cant be prevented

IV.
Need insulin therapy
T2DM
I.
Cause: insulin resistance
o Due to environmental factors
II.
Tend to develop at older age
III.
Can be prevented with lifestyle changes
IV.
Can be managed with lifestyle modifications alon if diagnosed early

 Hypoglycemia





=abnormally low BG conc
I.
low blood glucose level (70 mg/dl or less)
caused by
I.
the administration of excessive insulin or insulin secretagogues,
II.
too little food, delayed or missed meals or snacks,
III.
increased exercise or other physical activity
IV.
alcohol intake without food
Symptoms:
I.
Weak, rapid heartbeat, sweating, anxiety, hunger, trembling
o Hypoglycemia can be difficult to diagnose because these typical symptoms can
be caused by many different health problems besides hypoglycemia. For
example, adrenaline (epinephrine) released as a result of anxiety and stress can
trigger the symptoms of hypoglycemia.
Cause
I.
Medication
II.
Pancreatic tumor
III.
Overuse of insulin
o If diabetes
IV.
alcohol abuse
o reduce glucose secretion frm liver
recommendation:
I.
replacing refined carbs with fiber-rich
o we wanna keep blood glucse lvl as stable as possible
o sugar stimulate insulin release  further reduce the blood glucose lvl
o
 Inborn Errors of Carbohydrate Metabolism

Affect the catabolism & anabolism of carbs
 Lactose Intolerance


A type of digestive disorder
I.
Absence of enzyme lactase in SI  no absorption
II.
Bcm nutrients for gut microbiota in colon (fermentation)
o  produce large amt of SCFA & gases (methane, CO2, hydrogen)  bloat,
diarrhea, abdominal cramps
III.
Unabsorbed lactose  act osmotically attract water  increase fecal water  diarrhea
IV.
The hydrogen gas may be absorbed by body and exhaled in the breath  diagnose
lactose intolerance with breath analyzed for hydrogen gas production after lactose
intake
Types:
i. PRIMARY (adult) lactose intolerance
I.
II.
Common
o Related to genes
Cause:
o Decrease in lactase production with age
 After weaning, our lactase may decrease
ii. Secondary lactose intolerance
III.
IV.

Rare
Cause:
o Illness (stomach bug/ celiac disease)
o Inflammation in gut wall  temporary decline in lactase
Solution
I.
Chew tablet (food enzyme dietary supplement)  Beano
o
o
natural enzyme alpha-galactosidase
break down carbs in beans into simple sugar  easier to digest
 Hereditary Fructose Intolerance





Inability to convert fructose  glucose due to deficiency of “fructose-1-phosphate aldolase”
I.
This enzyme is found in liver, kidney & mucous membrane of SI
II.
Causing  Intracellular accumulation of fructose-1-phosphate  toxic liver cell
death
Symptoms: (when eating fructose  accumulation)
I.
Nausea, bloating, abs pain, diarrhea, vomiting
II.
hypoglycemia
o accumulation may inhibit of glycolysis & gluconeogenesis
 fructose-1-phosphase cant be broken down to maintain blood sugar
 trapping of phosphate  reduce ATP production
III.
toxic effect if repetitive ingestion of fructose
o on liver, kidney, SI
Infants
I.
Failure to thrive
II.
if you notice when infant is introduced with fruits and experience those symptoms then
it may be due to fructose intolerance
repetitive consumption of fructose-containing food  kidney/ liver damage
food contain fructose
I.
sucrose, sorbitol
II.
fruits
 Dietary Fiber



Hipsley=non-digestible constituents making up the plant cell wall
latest def= fraction of edible part of plants/their extracts/ analogous carbs, that are resist to digestion &
absorption in the SI, usually with complete/partial fermentation in the LI
types:




Function:

Health benefit approved by FDA:
I.
along with a decreased consumption of fats (<30% of calories), an increased consumption of
dietary fiber from fruits, vegetables and whole grains may reduce some types of cancer
a. Increase fiber consumption
i. = six or more “one-ounce equivalents”, with three ounces derived from
whole grains. A one-ounce equivalent would be consistent with one slice
of bread, ½ cup oatmeal or rice, or five to seven crackers
b. 1 ounce – 28g
II.
c.
Diets low in saturated fat & chol & increase in F&V & whole grain  reduce risk of CHD
 ~25-35g/d of which 6g are soluble fiber
Water-holding/hydration capacity and viscosity


= the ability to bind water and form viscous, slow-moving solution within GIT
Factors:
 Soluble > insoluble
 Degree of processed
 Coarse > fine

Effect:
1. Delay gastric empty
 Postprandial satiety
 Slow down digestion and carbs and lipid are not digest in stomach
2. Reduce mixing of GI content with digestive enzyme
 Reduce enzyme function
 Form a physical barrier trapping nutrient to touch with enzyme
3. Decreased nutrient diffusion rate  attenuate blood glucose response
 Thicken the unstirred water layer by the viscous fiber solution  retard the rate of diffusion of nutrients
into enterocyte
 Certain fiber affect the release of hormone
 Fiber: gums, pectin, beta-glucan, psyllium , resistant starch
 Hormone: glucagon like peptide 1 & insulin
I.
GLP1
o Promote tissue utilization of glucose
o High fiber increase GLP1  reduce insulin needs
o This is beneficial for DM who is insulin resistant
II.
Application:
o Some DM friendly food may midified the starch of the food to  resistant
starch
 So that DM can enjoy cabrs without excessive elevation in blood glucose
conc and inslin needs
4. Increase transit time  slower the movement of the food
 Soluble delay, insoluble increase
 If shorten  decrease nutrient absorption
Adsorption or Binding Ability

The ability to bind to substances such as enzymes / nutrients in GI

effect:
1. diminished absorption of lipids
 fiber adsorb FA, chol, bile acid  cannot form micelles  X be absorbed bcs need to be in micelles form
to be transported across the unstirred water layers  excreted in feces
2. increased fecal bile acid excretion
 fiber-bound bile acid X be reabsorbed to enterophepatic recirculation  excrete in feces
3. lowered serum cholesterol concentrations (hypocholesterolemia properties)
a. increase excretion of bile acid & chol in feces
a. decreased hepatic chol  promote removal of LDL from blood to increase hepatic chol to
form new bile acid
b. production of SCFA
a. inhibit FA & chol synthesis
4. altered mineral, carotenoid, and phytochemical absorption
 some fibers (hemicellulose, pectin, gums) + fructose, galactose, oligosaccharides  form catonic bridges
with minerals in GIT
 the overall effect (negative/positive) depend on the degree of fermentability or accessibility to bacterial
enzymes in the colon
 acidic environment generated by fermentation  aids in mineral solubility
I.
Ca, Mg, Zn, Fe bound to fiber may be released in colon  absorbed
 Negative effect on
I.
Carotenoid
II.
Phytochemicals

Improve phytochemical absorption through bacterial action
I.
Polyphenol as conjugated glycosides may be converted  unconjugated by bacterial
action
II.
Aglycone are better absorbed
Fermentable fibers
a. Prebiotics
 Not all fermentable fibers are prebiotic
 = promote the colonic growth or activity of selected health-promoting species of bacteria
 Include:
 Fructans (inulin, oligofructose, fructooligosaccharides)
 Galactose
 Lactulose
 Soybean oligosaccharides (raffinose, stachyose, verbascose)
b. SCFA


Acetic, butyric, propionic acides
Roles:
 Increase water & Na absorption in colon
 Mucosal cell differentiation & proliferation
 Acidify luminal environment
 Provision of energy
 Inhibit chol synthesis
 Improve colonic blood flow
 Enhance immune function
Nonfermentable fiber
a. Detoxification
 Insoluble fiber adsorb hydrophobic carcinogen to prevent their interaction with colonic mucosa
b. Increased fecal volume
 Dietary carbohydrates and dental caries


Dental caries (tooth decay) = activity of certain species of bac that live in dental plague
 Streptococcus mutans & S.sobrinus
Stage:
I.
Initial demineralization
i. Enamel: hardest tissue in our body
1. Made of minerals
ii. When enamel exposed to acid  lose minerals
II.
Enamel decay
i. White spots on tooth darken to brownish color
ii. Small hole form in teeth  Formation of cavities/ dental caries
III.
Dentin decay
i. Dentin: tissue lie under enamel
ii. (softer)  sensitive to damage from acid  faster rate of tooth decay
IV.
Pulp damage
i. Pulp: innermost layer of tooth
ii. Contain many nerves & bv  imp to keep the tooth healthy
iii. Damage  tooth pain
V.
Abscess formation
i. Abscess: a pocket of pus forming at the bottom of the tooth
ii. Swelling of gum, face, jaw, fever, swallon


Main cause:
 High-sugar food
I.
Bac ferment sugar producing acid
II.
Food Factor:
o Time of food in mouth
o Stickiness
o Frequency of sugar consumption
 Nutritive & Non-nutritive Sweeteners
 Artificial sweeteners



Non-nutritive sweeteners
Insignificant energy virtually no energy
Eg:
 Aspartame
 Cyclamate
 Saccharin
 Sucralose
 Stevia

Herbal products
 Derived from the leaves
 GRAS safety
 Sugar alcohols


Used in commercial food products
 Normally will label as “sugar-free” =/ calorie free
Nutritive sweeteners:

 sugar alc still provide kcal, but fewer than sugar
benefit:
 lower glycemic response
 body absorb sugar alc slower
side effect:
 intestinal gas
 abs discomfort
 diarrhea **
o food label have to mention” excess consumption have a laxative effect”

eg:


relative sweetness:
o compare the sweetness of sugar alc > table sugar
o smaller than 1  less sweet than table sugar
 isomalt  half of the sweetness of table sugar
 but the energy also half of it  macam no dif lo
 xylitol  same sweet as table sugar with half of the kcal of sugar
 but have some side effect like diarrhea!
o
T1- protein

Why 0 sugar still got kcal?
 Substitution of sugar alcohol (nutritive sweetener)
Amino acids:



~20 amino acids with different side groups  a protein
Source:
 Animal
 Meat, poultry, fish, eggs, dairy products (except butter, sour cream, cream cheese)
 Plant
 Grains, grains product, legumes, vegetable
 Endogenous protein presented to digestive tract
 Desquamated mucosal cells
 Digestive enzyme & glycoprotein frm digestive secretion
Structure:
 Central carbon + at least 1 amino group (-NH2) + at least 1 carboxy grp (-COOH) + 1 side chain (R group)
 All have same structure but different side groups


That’s why have dif
 Size, shape, electrical charge
1. Essential amino acids



Human body X synthesize at all/ insufficient quantity to meet its needs
Obtained from diet
VILLa HM = Ten Thousands Pounds
2. Nonessential amino acids


Can be syn in body
From Nitrogen & fragments of carbs/ fat
3. Conditionally essential amino acids: (6)

Under special condition
 Nonessential AA  conditionally essential AA
 When the need for it exceeds the body’s ability to produce it
 Liver disease (cirrhosis)
 Neonates born prematurely  immature organ function  X synthesis some
nonessential AA
 Phenylketonuria PKU


How to know the content of amino acid in food?
 Use HPLC
Digestion & absorption

Ultimate goal:
 Absorb & utilize AA
 The purpose of protein digestion is to liberate the amino acids from the consumed proteins
 in babies:
 protein can be absorbed in intact
 Prior to gut closure, the neonate can absorb some proteins. Most of these proteins are
immunoglobulins.
1. Mouth:
a. Protein is crushed & moistened
b. No real action of digestion
2. Stomach
a. HCL
i. Denature protein: (Partial hydrolysis of protein )
1. Uncoils (denatures) protein’s tangled strands  so that the digestive enzymes can
attack the peptide bonds
2. Peptide bonds not affected
ii. Activate enzyme pepsinogen  pepsin
1. Unactivated enzyme= zymogen / proenzyme
b. Pepsin:
i. Convert large polypeptides  smaller polypeptides & some AA
ii. Works under pH <~3.5
3. Small intestine:
a. Hormone:
i. Secretin + cholecystokinin
1. Stimulate secretion of pancreatic juice
a. Bicarbonate, electrolytes, water, proenzyme (X active in pancreases)
2. Stimulate enterocyte secrete mucus-rich secretion + enteropeptidase
b. Enteropeptidase
i. Activate trypsin  trypsin activate other proenzyme
c. Pancreatic & intestinal protease
i. Further hydrolyze polypeptides  short peptide chains, tripeptides, dipeptides, AA
d. Enzyme peptidase
i. Secrete frm membrane surface of intestinal cell
ii. Split most dipeptides, tripeptides  single amino acid
4. Absorption
a. Site:
i. duodenum
ii. upper jejunum
b. metabolites:
i. amino acids
1. less effective absorption than peptide
2. EAA absorb faster than NAA
3. Neutral > basic/acidic
4. Branched > smaller AA
5. Ingesting large amt of one AA  impair absorption of other AAs
a. Bcs they may be using the same carrier system
ii. peptide
1. more rapid absorption than AA
2. majority of AA is absorbed in peptide form into enterocyte
3. enterocyte breakdown peptide  AA intracellularly  release to blood
c. mechanism:
i. Specific carriers (most)
1. Transport AA into intestinal cells
2. Most of them are Na-dependent transporter
ii. (few) paracellular absorption
5. In enterocytes, AA
a. may be used for energy
b. synthesize needed compounds
i. structural proteins
ii. nucleotides
iii. apoproteins necessary for lipoprotein (chylomicron) formation
iv. new digestive enzymes
v. hormones
vi. nitrogen-containing compounds
c. unused aa  transport across cell membrane into the surrounding fluid where they enter the capillaries
 Transport to
i. Primary: liver
1. Monitor & adjust rate of metabolism (cata/ anabolism)
2. Main site for catabolism of EAA
a. Except BCAA  tend to be utilized by muscle & heart
ii. Other: kidney, other organ
Metabolism & utilization
1. Protein turnover (PT) & the amino acid pool (AAP)



PT: the degradation & synthesis of protein (2 process)
 Occur within each cell
AA pool
 The made up of AA in this pool is relatively constant
 Despite difference in protein intake & rate of degradation of tissue protein
 Source of AA pool (mix tgt)
 Dietary protein
 Endogenous AA from breakdown of body tissue
 AA pool includes:
 AA in plasma
 AA in cytosol of body cells
Regardless of the source (protein breakdown / dietary protein), all AA can be
 Used to make
 NEAA
 protein
 nitrogen-containing compounds
 neurotransmitter
 hormones
 glucose
 fatty acids
 ketones
 Stripped of their N  used for energy
2. Nitrogen balance (assessment of protein needs)




Amt of nitrogen consumed (N in) as protein as compared with the amt of N excrete (N out) in a given
period of time
 Only protein contains N atom, carbs & fat X have
 Protein contains ~ 16% Nitrogen
To estimate protein requirement
Calculation
 Nitrogen intake
 = protein intake * 0.16  protein intake(g)/ 6.25
 Nitrogen loss
 (U)urine
 (F)feces
 (S)skin
 nitrogen balance/ status = In − [(U − Ue) + (F − Fe) + S].
 e= endogenous = losses of nitrogen of subject under nitrogen-free diet
Output
 Nitrogen equilibrium
 N in = N out


Positive nitrogen
 N in > N out
o When our body need extra protein
o Pregnant, growing infants, children, adolescents, ppl recovering frm protein
deficiency / illness
 Negative nitrogen
 N in < N out
o Due to protein breakdown (muscles)  to produce energy
o Starvation, suffering from severe stress (burns, injuries, infections)
Disadvantage:
 Nitrogen balance =/ amino acid balance
 Overestimate true nitrogen retention rates in body
 Due to Incomplete collection & measurement of losses
3. Using amino acids to make other compounds
a. Tyrosine (precursor= phenylalanine  no enzyme converts p T in PKU)
i. Neurotransmitters (nervous system message)
1. Norepinephrine
2. Epinephrine
ii. Pigment melanin
1. In melanocytes in skin, eye, hair cells
2. Imp for hair, eye, skin color
iii. Hormone thyroxin
1. In thyroid gland + iodine
2. Metabolic rate
b. Tryptophan
i. Precursor for vit niacin (not very efficient)
ii. Precursor for serotonin
1. Appetite regulator
iii. Precursor of melatonin
1. In pineal gland
2. Regulate circadian rhythms & sleep
4. Using AA for energy & glucose


AA not used for synthesizing other compound  deaminated  carbon unit (keto acid) used for energy
 Keto acid=
Gluconeogenesis
 Protein can use to make glucose to provide energy
 Under carb deficiency + deplete glycogen
 This process should be avoided la  will break down muscle
5. Using AA to make fat


Excess glucose will store as glycogen (storage phase)  but X storage phase for protein  stored as fat
Energy & Protein intake exceed needs + carbs intake is adequate  store as fat
 Excess AA can convert to fat & stored for later use
Amino Acid Catabolism:

Involve 2 process: transamination & deamination (-NH2)

Deamination


o
Removal of amino grp (-NH2) from an AA (“Normally” essential AA )
Products:
 Ammonia NH3
o Needed to provide N for synthesis of NAA from keto acid
 Keto acid
o Use to produce a particular NAA
o

Transamination: (synthesis of NEAA)


Catalyze by aminotransferases/transaminases
o Cofactor: B6 (pyridoxal phosphate PLP)
o High conc in lover, normally low serum lvl
 Liver damage high serum AST & ALT



Amino group  excrete or use for N-containing comp production
Keto acid
 Produce energy (when diet inadequate in energy)
 Gluconeogenesis
 Only glucogenic AA
o = catabolism of AA must yield pyruvate or intermediates of TCA cycle
o Not all types of AA can be used to synthesis glucose
o Some of the carbon skeleton of certain type of AA can be used to produce
glucose
 Oxaloacetate  Carbon Skeleton of aspartate
 Pyruvate  Carbon Skeleton of alanine
 Bth Oxa anf pyruvate are used to produce glucose
 Primarily in liver, but also kidney & SI
 Speed up by high glucagon conc (due to low blood glucose)
o In between meals
o Fasting cause liver glycogen storage deplete
o Infection/ trauma/injury
o
 Ketogenesis:
 Ketogenic AA
o Catabolism of AA must generate acetyl-CoA or acetoacetate  used to form
keto bodies
 Fatty acid production
 Excess energy & protein intake + adequate carbohydrate intake

 A new nonessential amino acid A is formed
Utilization:
1. Growth & maintenance (anabolism)


Building blocks for most body structures
Replace dead/ damaged cells
 Life span of skin cell: 30days

 New cells made largely of protein grow frm underneath  replace old skin cells
 Muscle cells  make new proteins to grow larger & stronger in response to exercise
Factor affecting anabolism:
 Anabolic substances  promote protein synthesis & prevent protein degradation
 Growth hormone
 Insulin
o ** the anabolic effect of insulin is greater extend if both cabrs & protein ar
coingested vs ingested alone individually.
 Catabolic  gluconeogenesis, ureagenesis
 Glucagon
 Cortisol
o Infection/trauma
 Epinephrine
2. Enzymes


Facilitate chemical reactions w/o being changed in the process
catalyst
3. Hormones




Some hormones are proteins
Various endocrine glands  release hormones in response to changes that challenge the body
The blood carries hormone  target tissue  elicit responses  restore/maintain normal conditions
Exp:
 Catecholamines  tyrosine
 Melatonin tryptophan
 Growth hormone  promote growth
 Insulin/glucagon
 Thyroxin (tyrosine + Iodine)  regulate body metabolic rate
 Calcitonin & parathyroid hormone  regulate blood Ca
 Antidiuretic hormone  regulate fluid & electrolyte balance
4. Regulators of fluid balance



Protein (albumin) helps attract & keep water inside a particular area  contribute to osmotic pressure
Critical illness / protein malnutrition  plasma protein leak into tissue  attract water  fluid
accumulation  tissue swelling  edema
A diminished capacity to deliver nutrients & O2 to cells & remove wastes
5. Acid-base regulators (buffer)




Maintain blood pH at 7.35-7.45 or other cellular pH
Protein  negative charges on surfaces
 Attract H+
By accepting & releasing H+  protein maintain acid-base balance of blood & body fluid
Extreme of acidosis & alkalosis  coma & death

6. Transporters


Transport protein carry
 Esp for vit & minerals
 Na+, K+-ATPase pump
 Nutrients
 Amino acid transporter in intestinal cell brush border
 Oxygen , Co2
 Hemoglobin
 TG, Chol
 Lipoprotein
Other transporter
 Albumin
 Relatively long half-life (14-18days)  indicator of protein status
 Transthyretin / prealbumin
 Retinol-binding protein
 Vit A
7. Structural Element
a. Contractile protein
i. Actin
ii. Myosin
b. Fibrous protein
i. Collagen
ii. Elasin
iii. Keratin
8. Antibodies
9. Acute Phase Responders


Liver synthesis Acute phase protein in response to infection (sepsis), injury, inflammation
Eg:
 C-reactive protein

10.





Role:



  used to evaluate inflammation in patients clinically
 Dramatically increase within few hours of inflammation
Fibronectin
Orosomucoid
Sitmulate IR
Promote wound healing
Chelating/ remove free Fe to prevent used by bacteria for growth
Source of energy
provide energy & glucose  starvation / insufficient carbs intake
Gluconeogenesis
 Body breaks down its tissue protein to make AA available for energy / glucose production
 Losing lean body tissue


Ketogenic:
 The catabolism of the AA must generate non-TCA cycle intermediates which are used for ketone
bodies formation such as
 Acetyl CoA
 Acetoacetate
Glucogenic
 The catabolism must yield selected intermediates of TCA cycle to be converted into glucose
 Pyruvate
 Oxaloacetate
 Succinyl CoA

Nutritive values of proteins




Protein quality of diet  affect how children grow & adult maintain their health
Affect by:
a. Digestibility
i. Protein source & other food eaten with it
1. Animal: 90-99%
2. Plant: 70-90%
b. Amino acid composition
i. Supply enough EAA
High quality protein:
 Dietary protein containing all EAA needed to support the body’s work
 Protein from animal
Limiting amino acid:
 The indispensable / essential AA that is present in the lowest quantity in the food

Deficiency:


Protein deficiency rarely occurs alone. Instead, it is often coupled with insufficient energy intake.
They differ in the severity of energy deficiency as shown in the figure below.
1. Marasmus




Condition:
 Chronic period of insufficient energy & protein, vitamins & minerals intake
Vulnerable ppl:
 Infant (6-18 month)  cessation of breastfed
 In overpopulated & impoverished areas
Characteristic
 Extremely thin  matchstick limbs  like old ppl
 Muscle wasting
 Adipose tissue wasting
 Prominent bones
 Indicators of visceral protein status
 Within normal range/ just below normal range (not decreased to extent seen in
kwashiorkor)
Complication:
 Impair brain development & learning ability
 Affect ppl in rapid growth
 Decrease synthesis of key hormone
 Growth hormone is made of protein
 Little / no fat under skin
 Reduce metabolism & btemp
 Mental & behavioral development retardation
 Growth ceases= stunt
 Good appetite possible
2. Kwashiorkor



Acute PEM= A sudden & recent deprivation of food
Condition:
 Typically ingest enough energy (usually as carbs)
 Insufficient protein
Characterized by:
 Inadequate visceral protein status




High insulin level prevents protein breakdown to form visceral protein
Low total protein conc in blood
o Albumin
o Retinol-binding protein
o Prealbumin
Consequence:
 Edema in limbs & abdomen
 Low protein conc water diffuse frm blood to interstitial spaces
 1st appear at legs  face  all over body
 Muscle mass, adipose mass may be normal
 Carbs intake stimulate insulin production  storage hormone  prevent fat
metabolism inhibit ketogenesis limiting adaptation to starvation
 Fatty liver
 X synthesis transport protein of lipids out of liver
 Reduce tyrosine for melanin  loss hair color
 Inadequate protein synthesis  skin patchy & scaly
 Loss of appetite
Susceptible population
 Children 1-3yo
 Developing country
 Extreme cases significantly increase protein need
 Burns
 Sepsi
 Trauma
 Following major surgery
Kwashiorkor vs Marasmus
3. Cachexia

A muscle loss & wasting condition that is associated with an underlying illness
 Cancer
 AIDs
 Multiple sclerosis
 Tuberculosis


Altered metabolic adaptation  proinflammatory cytokines & resting energy expenditure
Loss of body weight, fatigue, weakness & loss of appetite
Inborn Errors of Protein Metabolism

Cause:
 Mutation in genes encoding key enzyme in AA metabolic pathway
 Total loss / partial loss of catalytic activity
 More than 50 AA metabolic disorder  majority are very rare
 Autosomal recessive inheritance
1. Phenylketonuria (PKU)
\


Inability of body to utilize phenylalanine (EAA)
 Due to defective activity of phenylalanine hydroxylase to convert phenylalanine Tyrosine

Consequence:
 Buildup of phenylalanine & its metabolites (phenylacetate, phenylpyruvate, phenylacetate) in
blood & other body fluid
  hyperphenylalaninemia



 Blood tyrosine conc diminish
Blood phenylalanine level
 Normal: ~1 mg/dL
 PKU: ~ 6-80mg/dL (usually > 30mg/dL)
Sign & symptom
 Mild severe
 Classic PKU  most severe form
 * infant with classic PKU appear normal until they are a few months old
w/o treatment
 permanent intellectual disability
 seizure
 delayed development
 behavioral prob
 psychiatric disorder
 musty/mouse-like odor
 hypopigmentation
 no tyrosine to form melanin


albinism 白化病
 eczema
treatment
 low intake of phenylalanine & aspartame
 aspartame nonnutritive sweetener made of aspartic acid + phenylalanine
 supplement of tyrosine
2. Homocystinuria



Autosomal recessive disease
Characterized by:
 Eye
 Myopia  ectopia lentis dislocated lense
 Skeletal system
 Too tall, slender
 Osteoporosis
 Vascular system
 Thromboembolism
 CNS
 Developmental delay
 Seizure
 Psychiatric problem
 Other
 Hypopigmentation of skin, hair
Cause:
 Genetical cause:
 Deficiency of enzyme cystathionine beta-synthase (vit B6 requiring enzyme)
o Convert homocysteine cysteine
o  accumulation of homocysteine & its metabolite in urine & blood
 Deficiency of MTHDF
o  methionine remethylation defects
o Convert homocysteine  methionine

o Folate & vitamin B12 dependent
 Abnormal cobalamin metabolism
non-genetical cause
 deficiency of cobalamin B12
 deficiency of pyridoxine B6

Methionine catabolism
1. Methionine is converted into  SAM (S-adenosyl methionine)
a. SAM is a principal methyl doner in body
b. Needed to synthesis of other substances
c. Used to methylate DNA
2. The removal/ donation of methyl grop from SAM  SAH (S-adenosyl homocysteine)
3. SAH  homocysteine
4. Homocysteine can be converted ack to methionine in 2 ways:
a. Betaine-dependent reaction
i. Generated in liver from choline
ii. Provide methyl group to homocysteine
b. Vitamin B12 (as methylcobalamin) + folate (as 5-methyl tetrahydrofolate)-dependent reaction
i. Methylcobalamin get the methyl frop from 5-methyl tetrahydrofolate (coenzyme form of folate)
ii. Methylcobalamin provides the methyl group to homocysteine to form methionine
 Methionine is the precursor of cysteine (conditionally EAA)
5. Homocysteine + serine –(cystathionine-synthase + vitamin B6) cystathionine
a. Vitamin B6 in coenzyme form (OKO) are needed for this process
6. Cystathionine  cysteine
 Methionine  homocysteine –X cysteine
o homocysteine can be reconverted into methionine with the help of (methyl
donor)
 Folate
 Betaine
 Choline oxidized to form betaine
o Homocysteine  cysteine
 Require Vit B6
 ** may be seen in patients with cobalamin B12 & folate deficiency
 cause:
i. deficiency of cobalamin


ii. deficiency of folate
iii. deficiency of cystathionine beta-synthase
w/o treatment:
 dislocated lenses
 cataract
 muscle weakness
 elevated homocysteine may interfere collagen corss-linking in bone  increase fracture
risk
 thrombosis
 due to homocysteine
 delay in the development & hypercoagulability
treatment
 Vitamin B6 therapy
 aids in homocysteine cysteine
 low dose of folic acid or folate + B12 supplement
 help in reversion of homocysteine --> methionine
 but the amt need to be controlled bcs it aids in both direction of
o methionine  homocysteine
 Unlike betaine, only aids in one direction
o homo --> methionine
 cysteine supplement
 methionine-free amino acid formula + cysteine supplement drinks
 betaine
 provide alternate remethylation pathway of homocysteine  methionine
 a low protein diet
7. Maple syrup urine disease





=branched-chain ketoaciduria
Autosomal recessive disease
Due to
 Deficiency of enzyme branched-chain alpha-keto acid dehydrogenase (BCKAD)
 Needed to metabolize BCAA (mostly in skeletal muscle)
o Leucine, isoleucine, valine
 Imp for muscle protein metabolism for energy & growth
Characterized by:
 Neurological & developmental delay
 Within brain, BCAA metabolism maintain glutamate level
o BCAA  transamination  form glutamate
o Glutamate  neurotransmitter within CNS  imp for brain development &
cognitive function
o Leucine accumulation is neurotoxin
 Maple syrup odor to urine
 Feeding problem
 Nausea, anorexia
Roles
 Valine  mental health & muscle coordination
 Leucine  regulate glucose in skeletal muscle & maintain the amt of muscle protein
 Isoleucine hemoglobin formation & regulate blood sugar level


W/o treatment
 Sweet-smelling urine
 Neurological damage
 Poor feeding
 Vomiting
 Dehydration
 Lethargy
 Hypotonia
 Seizure
 Ketoacidosis
 Pancreatitis
 Coma
Treatment
 Diet low in BCAA (not completely cut off)
 Thiamin supplement
 Thiamin is needed for BCKAD as coenzyme
T3- Fat

Lipid


Insoluble in water
Type:
 Triglyceride:
 Fat in food
 Made up:
o 1 glycerol
o 3 fatty acids
 Phospholipids
 Made of:
o 1 glycerol
o 2 fatty acids
o 1 phosphate group
 Hydrophilic  sol in water
 Make phospholipid sol in hydrophobic/hydrophilic environment
 Emulsifier
 Sterol
 Multiple ring structure
 No fatty acids
 Found in
o Animal
 Cholesterol
o Plant
 Phytosterol
Food source:

Visible
 Marbling in meat
 Butter
 Oil

invisible
 fat in whole milk
 eggs
 whole grain
 baked products
 convenience food
Fatty acids:



An organic acid
Consist of:

 Carboxylic acid (-COOH)  alpha end
 Methyl grp (-CH3)  omega end
Differentiate by:
 Carbon chain length
 Degree of saturation
1. Carbon chain length



Most naturally occurring FA  even numbers of Carbon
Classified:
 Long chain (12-24C)
 Most of your food is LCFA
 Medium chain (6-10C)
 coconut
 Short-chain (<6 c)
Carbon Chain length lower, melting point lower  liquid
2. Degree of Saturation



Saturation= Whether or not a fatty acid chain is filled to capacity with hydrogen atoms
SFA
 only single bonds between C
 fully loaded with H


 Point of unsaturation = where H atoms are missing on the chain
More saturated FA  solid
More unsaturated FA  liquid in room temp


Visible & invisible fat
 Butter is visible fat which we will straight relate to fat but walnut as invisible fat also
very high in fat
 Plant higher in unsaturated FA  animal higher in saturated FA
Essential FA



Needed by the body but not made by it in amt sufficient to meet physiological needs
2 EFA
 Linoleic acid n-6
 Alpha-linolenic acid n-3
Cell X possess enzymes to
 Make o-6 & 3 FA frm scratch
 Convert o-6  o=3 or vice versa
 Whereas o-6 can be converted to other complex FA via (but the conversion rate is very slow  X
solely depend on the dietary O-6 for arachidonic acid)
 Elongation
 Desaturation
Omega-6 FA



Primary member: linoleic acid (precursor for complex O6FA)
When body get LA frm diet make other members of O-6 family
 Conditionally essential FA
 When LA deficient  all other FA derived frm LA  conditionally EFA  need to obtain frm diet
Types: (major 4  still many more types)

Omega 3 FA

Primary member: alpha-linolenic acid
 Can be converted into
 EPA (eicosapentaenoic acid)
 20C


 8-21% CONVERSION
 DHA (Docosahexaenoic acid)
 22C
 0-9% conversion
 Can be considered conditionally EFA
 ** imp for :
 Eyer & brain
 Normal growth & cognitive development
Conversion competes with the same enzymes in omega 6 pathway (elongase, desaturase)
  further decrease the conversion rate
 ** food source  effective way to maintain O-3 & O-6 bod supplies
Type:

EFA deficiency
1. Skin
a. Scaly, dry skin
2. Weight
a. Decrease
3. Circulation
a. Heart enlargement; decreased capillary resistance (lower blood pressure at periphery); increased
permeability
4. Kidney
a. Enlargement; intertubular hemorrhage
5. Lung
a. Cholesterol accumulation
6. Endocrine glands
a. Adrenals: weight decreased in females and increased in males
b. Thyroid: reduced weight
7. Reproduction
a. Females: irregular estrus and impaired reproduction and lactation
b. Males: degeneration of semini-ferrous tubules
8. Metabolism
a. Changes in fatty acid composition of most organs
b. Increase in cholesterol levels in liver, adrenals, and skin
c. Decrease in plasma cholesterol
d. Changes in swelling of heart and liver mitochondria and uncoupling of oxidative phosphorylation
e. Increased triglyceride synthesis and release by the liver
Digestion & Absorption:

GI tract receives
 50-100 TG
 4-8g phospholipid
 200-350mg cholesterol
1. Mouth
a. Lingual lipase released (not actioned)
i. Acid-stable (stomach HCl)
b. Physical state: Mastication of food  mix lingual lipase with food
2. Stomach (2-4hours)
a. Physical state: churning of stomach  mix food with HCl  separate lipid particles  exposing more
surface area for enzyme action & emulsion formation
i. Lipid-protein complexes are cleaved by
1. HCL denaturation
2. attack of gastric protease
b. Gastric lipase
i. Minimally breakdown triglyceride (only 30%)  diglyceride & fatty acid
1. Bcs most of the lipid floats above the watery content of swallowed food
c. Activation of lingual lipase
i. Limited effect  due to tendency of lipid to coalesce & form a separate phase
ii. Digested lipid by them  release single fatty acid (short/medium chain FA) + diacylglycerol
1. Imp for infant
a. Milk= main source mostly s/mcfa
b. Immature duodenal lipase
2. Less imp for adult
a. Mix diet
iii. The Released diacylglycerol + s/mcfa  emulsifier/surfactants  stabilize emulsion  produce
chyme  expelled into duodenum
3. Small intestine:
a. Hormone: (stimulate by chyme’s entry)
i. Cholecystokinin  stimulate gall bladder to contract  release bile
ii. Pancreozymin  stimulate pancreas  pancreatic juice (lipase)
b. Physical state:
i. Bile salt (not bile) = emulsifying agent due to its amphipathic properties  further Disperse lipid
droplet frm stomach  micelles  facilitate hydrolysis of glycerides by pancreatic lipase (Such
molecules tend to arrange themselves on the surface of small fat particles, with their
hydrophobic ends turned inward and their hydrophilic regions turned outward toward the water
phase. This chemical action, together with the help of peristaltic agitation, converts the fat into
small droplets with a greatly increased surface area.)
1. Bile salt impart negative charge to lipid  attract pancreatic lipase
2.
c. Pancreatic lipase
i. Remove the fatty acids of triglyceride  monoglyceride & a glycerol, fatty acid
 An inhibitor of gastric and pancreatic lipase, orlistat, has been developed to reduce the
absorption of dietary triacylglycerols. It is marketed both as Xenical, a prescription-only
product, and Alli, an over-the-counter product. The rationale for use is that when the
hydrolysis of TAG is restricted, less dietary fat will be absorbed, resulting in decreased
caloric intake. Xenical inhibits the absorption about 30% or by 200 kcal from fat per day.
d. Absorption:
i. Stabilized by the polar bile salt, the micellar particles are sufficiently water soluble to penetrate
the unstirred water layer that bathes the enterocytes of the small intestine  Micelles transfer
digested products  brush border
1. SCFA  simple diffusion through epithelial cells  blood
2. LCFA/ monoglyceride unpack frm micelles  simple diffusion  in cell, repacked into
triglyceride  packaged + fat-sol vitamin as chylomicron  lacteal of villus  circulate
in lymphatic circulation  left at left subclavian vein  hepatic vein liver
a. Chylomicron= large TAG-rich spherical particles containing TAG, cholesteryl
esters, phospholipids (PL), and vitamins A and E in the core and a monolayer of
PL, free cholesterol, and protein on the surface
4. Large intestine:
a. Some fat & cholesterol trapped in fiber (adsorbent)  exist in feces
i. Esp soluble fiber able to form gel-like consistency of chyme
5. Bile:
a.
Metabolism & Utilization:
1. Adipose cells store fat after meals


Chylomicrons circulate  reach tissue that using lipid as fuel TG hydrolyze by lipoprotein lipase
frm lipoprotein  Fatty acid, diglycerides, monoglycerides enter adipose cell TG reassembled
inside adipose cells
To store energy
2. Using fat for energy


Energy deprivation  stored TG released glycerol & FA directly into blood
Body cell use these compounds to yield energy, CO2, water
Catabolism of TAG & FA



Glycerol + 3 FA
Glycerol
o Used for energy by liver and other tissue having enzyme glcerokinase
 Convert to glycerl phosphate enter glycolytic pathway at the level of
dihydroxyacetone phosphate  enter energy oxidation or glyconeogenesis
Fatty acid
o Very rich source of energy
o Mechanism = beta-oxidation
o Step:
 Enter the cell of metabolizing tissue  activated by coenzyme A
 Mitochondrial transfer of Acyl CoA
 Oxidation of FA is in mitochondria

 SCFA can pass directly in
 LCFA need the help of carnitine (carrier molecule)
 Beta-oxidation Yielding acetyl CoA
 Acetyl CoA then enter krebs cycle to produce energy
Ketone bodies formation
o Other than direct oxidation through kreb cycle, acetyl-Co A may follow other catabolic
routes in the liver to make ketone bodies
 Acetoacetate, beta-hydroxybutyrate, acetone
o KB are not oxidized in the liver, but transported by blood to other tissue that contain
enzyme to reconvert KB back to acetyl CoA to enter krebs cycle
o This is a “overflow” pathways for acetyl CoA
 Giving another way for liver to distribute the fuel to peripheral cells
 Eg:
o Accelerated fatty acid oxidation
o Low carb intake
o Impaired carbs used
o DM
o Starvation
o Why low carbs leat to KB ?
 Without oxidation of glucose, the supply of oxaloaxetate is reduced
 Oxa is needed to bind with acetyl-CoA to enter kreb cycle
 As low carb also induce FA oxidation  overload with acetyl-CoA, but cannot enter
kreb cycle directly only can form ketone body to lower acetyl-CoA
3. Insulating & protecting

>=30% body weight = adipose tissue
o Visceral fat= protect vital organs
o Subcutaneous fat= insulate body from extreme temp & keep internal climate under control
 Pads the hands & buttocks
 Prevent friction
4. Regulating & signaling




Hormones
Adipose tissue secretes hormone leptin to regulate appetite
Reproductive health  infertile
Sustain nerve impulse transmission, memory storage & tissue structure
5. Maintain cell membranes

Cell membrane is made of
o Phospholipid  bilayer
Cholesterol
1. Food source:


Dietary chol= main steroid frm animal tissues
Top 5



o Egg & its dish
o Chicken
o Beef & its dish
o Burgers
o Cheese
Source contribute to liver cholesterol pool
o Dietary (exogenous)
 Transport as chylomicron
o De novo (endogenous)
 Transport as VLDL, LDL, HDL
It is not an energy-producing nutrient
The main excretion pathway
o Via bile excretion
2. Function



Precursor of other steroids
o Cholesterol is the most common sterol in animals and is the precursor for other steroids.
a. bile acids
b. steroid sex hormones (estrogens, androgens, and progesterone)
c. the adrenocortical hormones;
d. vitamin D (cholecalciferol)
form & maintain cell membrane & structures
o particularly of nerve cell
nerve cell insulation
3. Relationship with chronic diseases


Dietary cholesterol  raise blood cholesterol  increase CVD
o Effect is not as strong as SFA & trans fat
Chol found in all animal food
o Eat less fa from animal food  lower dietary chol + SFA
Transport of lipids

Lipoproteins
o Clusters of lipid associated with proteins that serves as transport vehicles for lipid in blood
1. Chylomicron:





Largest & least dense
not synthesized by liver but enterocyte
Role:
o Transport dietary lipids frm SI to tissues
o The role of the chylomicron is to deliver dietary lipid mostly to tissues other than the liver, such as
muscle and adipose tissue (80%). Much of the remaining lipid (20%) is delivered to the liver in the
form of chylomicron remnants
transported by the blood throughout all tissues in the body--> intravascular hydrolysis at certain tissue sites
(lipoprotein lipase) at endothelial cell surface of the small blood vessels and capillaries primarily in adipose
tissue and muscle (but not in the liver)
The part of the chylomicron that is left following this lipolytic action = chylomicron remnant (a smaller
particle, relatively lower in triacylglycerol, but richer in cholesterol and cholesteryl esters)  removed from
the bloodstream by hepatocyte endocytosis
2. VLDL



Role:
 Transport lipid frm liver to tissues
is made of endogenous TAG
 chylomicron remnant
 cholesterol carried back by LDL from previous cycle that carried out by last VLDL but not
deposited in the body tissue
The removal of TAG frm VLDL continues until a cholesterol-rich LDL particle remains.
Undeposited VLDL (yellow dots)



LDL will carry back to the cycle again to get a chance to be deposited
If still not deposited  LDL carried back to liver to be made again into VLDL
HDL carried back to liver to be excreted
Cloud-circled one = similar

 The chylomicron remnant enters into the hepatocyte in the same manner as LDL
The fasting serum VLDL is very low
 Bcs is quickly metabolized into IDL/ LDL
3. HDL



Role: carry chol out of bloodstream into liver (reverse cholesterol transport)
Made by liver to take up the chol that is not deposited back to liver
To be made into other useful metabolite
 To make vit D etc..
 For other usage
4. LDL


Transport Chol & other lipid frm liver to tissues
 Bind 60% of the blood chol
 Provide chol for dif tissue to make
 Membraine
 Convert to other metabolite such as hormone
 These tissue has to have LDL receptor
 One of them is endothelium  fatty plague
When VLDL has distributed the TG content to other tissue, the remaining bcm LDL  cholesterol rich
 LDL is one of the major lipoprotein during fasting serum
The concentration of cholesterol
Liver in fat metabolism:
1. site of synthesis of lipoprotein (the other is enterocyte--> chylomicron)
2. synthesize new lipids from nonlipid precursors (glucose/ AA)
3. take up & catabolize dietary lipid (in the form of chylomicron remnants/ MCT/LDL)--> repack them into HDL/
VLDL forms
 high carbs (esp simple sugar) --> accelerate hepatic TAG production frm glucose --> observe
hypertriacylglycerolemia in healthy ppl when they consume high simple sugar diet
 Cholesterol and cholesteryl esters from the chylomicron remnant may be used in several ways
1. converted to bile salts and secreted in the bile
2. secreted into the bile as neutral sterol (such as cholesterol or cholesteryl ester)
3. incorporated into VLDL or HDL and released into the blood
beneficial effect of omega 3, 6, 9 fatty acids





replace both SFA & trans fat with mono & polyUFA  heat disease prevention
low rate of heart disease in Mediterranean region  olive oil
1. MUFA & phytochemicals (rich in virgin olive oil)
Omega 3  reduce risk of heart disease & stroke
1. Prevent blood clots
2. Protein against irregular heartbeats
3. Lower blood pressure
4. Healthy immune system
5. Defend against inflammatory disorder
American heart association recommendation:
1. 2 serving of fatty fish a week
 Grill, bake, broil
 X fried & frozen fried  reduce omega 3, increase trans & SFA
2. Combine with physical activity
Supplement of fish oil
1. Routine supplementation is not recommended
2. Overdosage:
 >3g perday

Complication
 Increase bleeding time
 Interfere with wound healing
 Raise LDL
 Suppress immune function
Trans fatty acids




characteristic: linear shape like saturated FA
How it's made:
o During the dehydrogenation process, electronic shifts cause remaining, unhydrogenated cis double
bonds to revert to a trans configuration that is energetically more stable
Zero trans-fat:
o use a blend of natural oils containing a chain length and unsaturation level that provide the desired
properties without any hydrogenation
o labeling regulations = >0.5 g of trans fat/ serving --> can result in consuming more than the
recommended level
impact:
o even more unfavorable than SFA
o increase LDL & chol + lower HDL
Ketosis




a metabolic process occurs when body begins to burn fat for energy
o liver produce ketones  supply to ketone-using tissue to be used as energy
condition:
o X enough carbohydrate
Common
o Diabetes
 Impaired insulin production  intracellular glucose deficiency
o Ketogenic diet
Outcome:
o Bad breath (acetone)
o Increase ketones in blood
o Appetite suppression
 Low insulin
o Initial short-term fatigue
o Digestive issue
o Insomnia
o Short-term decrease in performance
o Ketonuria
o Weight loss
o Increased focus & energy

Dietary lipids & Atherosclerosis




Excess intake of SFA, trans-fat, chol  CVD
Saturated fat
o Increase LDL-cholesterol
 more SFA --> increase chylomicron remnant + unused up VLDL--> increase formation of LDL
circulating in the blood

Trans-fat
o Increase LDL
o Decrease HDL
Cholesterol
o Effect of increase blood chol  increase risk of CvD not so strong as SFA & trans fat
o The reason why chol is considered the culprit for CVD is due to that it is the major component of fatty
plague
o But dietary chol only has minor influence on blood chol conc in most ppl
 Bcs compensatory mechanism like
 HDL activity in scavenging excess chol
 Down-regulation of chol synthesis by dietary chol
o Genetic also play a vital role
 Some is hypo/hyperesponders to chol
Dietary Lipids & Cancer




Lesser relationship between lipid intake & initiate cancer development
o But promote cancer once it has arisen
Differ in Types of cancer:
o Breast cancer
 Weak & inconclusive evidence
 More convincing evidence= body fat contributes to the risk
o Colon cancer
 Limited evidence
Differ in types & combination of fat
o SFA or fat from meat  increase cancer risk
o Fat from milk. Fish  not implicate in cancer risk
 O-3 suppress inflammation  may protect against some cancer
Dietary advice to reducte cancer risk = same as for reduction of heart disease
o Replace SFA with USF + increase O-3
Fat Substitutes
1. Fat replacers

ingredients that replace some or all of the functions of fat & may /may not provide energy
o Less than 9kcal/g
a. Carbs-based

Thickeners / stabilizers
o Soup & salad dressings
b. Protein-based

Creamy feeling
o Ice cream & yogurts
c. Fat-based

Emulsifiers & heat stable
o shortenings
2. Artificial fat
o
o
o
= zero-energy fat replacers that are chemically synthesized to mimic the sensory & cooking qualities of
naturally occurring fats but resistant to digestion
Olestra
 A sucrose mol with 6-8 fatty acids
 X breakdown by digestive enzyme
Concern of FDA
 Is olestra toxic?
 No reports of cancer or birth defects
 Affect nutrient absorption & health of digestive tract?
 It binds some fat-sol vit & carries them out of body
o Hence products with olestra need to fortify with fat-sol vit
 May experience digestive distress
o
Initially FDA required warning label of olestra  now no need
T4- Vitamin A
Fat soluble vitamins:
 Similar to fat in metabolism and transportation
 Require bile to form micelles
 Store in adipose tissue…
Introduction


1st vitamin identified as essential micronutrients
=a term for the biologically active compound retinol & its provitamin (precursor) carotenoids
Food sources


Carotenes (pro-vitamin A) are found in plant
o But more than 600 members of carotene family of pigment found, only 550-60% can be converted into
vitamin A than can be used by our body
Plant source (pro-vitamin A)
o

o
Animal (vitamin A)
o
nomenclature & structure




Vitamin A not just single compound  many forms
If they have the same similar chemical structure  provide the possible activity in body
Exp:
o Natural:
 Retinol
 Retinal
 Carotene (alpha, beta, gamma)
o Synthetic:
 Retinyl acetate
 Retinyl palmitate
Chemical structure:
o Essential if a compound is to have vitamin activity
 Any changes  reduce vitamin A activity
o
Consist:
 Beta-ionone ring
 Oxidation
o Reduce vit ac
 Demethylation
o Reduce vit ac
 Side chain= Isoprenoid chain
 Length may affect the vitamin activity  too long/ short  lost activity
 Saturation
o Unsaturated bond  saturated may reduce activity
 Isomerization
o Reduce the vit activity
** all these 7 structures are carotenoids as they can be found in colored plant, but not all of
them are provitamin



o
Potency:
For a chemical comp o be characterized as vit A, need 2 structures:
o Beta ionone ring
o Isoprenoid side chain
For exp:
o Beta carotene (most potent)
 In body, it will be split into 2 as it is symmetrical  produce 2 vitamin A
 Because ut has 2 beta ionone rings, and the side chain can be divided
into 2
o Alpha carotene
 The right ring is not original beta ionone ring  has been hydrogenated
 cannot undergoes vitamin A activity  only left side has the vit A
activity  not so potent compare to beta carotene which can produce 2
vit A
o Beta-Cryptoxanthin
 Has the potential to bcm provitamin  be converted into functional
vitamin A in the body as it has a proper beta ionone ring
o For lycopene, lutein, zeaxanthin not provitamin A
 They don’t have beta-ionone ring
** carotenoid can be classified as:
o Provitamin A carotenoid
 Beta- carotene
 Alpha- carotene
 Gamma- carotene
 Beta- cryptoxanthin
o Non-provitamin A carotenoid
 Lutein
 Zeaxanthin
 Lycopene


** we can’t say beta-carotene has the same potency as retinol
 Not 100% beta-ca consumed is absorbed & converted into retinol
 Hence the activity is ard 50% of retinol activity
Requirement



Affected by the potency of the ceratoid
Hence we need to compare the reference= retinol  retinol equivalent (RE)
o 1 RE =
 1ug retinol
 6ug beta-carotene
 12ug alpha carotene
 3.33IU (international unit)
RNI:
o
o
o
Metabolism
 Absorption
o
o

Most at duodenum
Not so effective as water-sol vit  need to go through lymphatic circulation 1st b4 entering systemic
circulation
o All-trans Retinol is most preferred form for absorption  highest absorption rate
o Require lipid & bile salt
Metabolism of retinol:
o
o
o
Retinol can be converted/reconverted into retinal
But retinoic acid cannot be reconverted back to other form
 Transport
o
RBP (retinol-binding protein)
 Specific protein that binds with retinol to transport them frm liver to the rest of body
 Produced in the liver
 The binding of RBP started frm liver, during the absorption and transport to liver  no RBP
 Once reach target tissue  bind to the receptors sie on the cell membrane
 Receptors for retinol / retinoic acid
 Retinol is released frm RBP  into the cell  bound to intracellular binding proteins
o
o

Deficiency
 In protein malnutrition children  reduce protein  reduce RBP synthesis
 Lead to Vitamin A deficiency
Higher level of RBP
 In kidney disease
 Kidney breakdown & eliminate protein including RBP
 Lead to vit A toxicity even if vit A intake is above normal
Function

Vision
o The production of rhodopsin in retina  imp for adaptation of vision in the dark
 Rhodopsin regulated by how much light intensity enter our eyers
 Convert the light into electrical signal
o All-trans retinol is transported (the only form)  retina cell  convert o all-trans retinal  isomerized
into 11-cis retinal  combine with opsin  frm rhodopsin
 Why transport as retinol?
 Retinol more stable
 The transport is by RBP  only can bind with retinol
 Retinol is the storage form



o
Growth
o Retinol, retinal, retinoic acid
Cell differentiation
o Retinol, retinal, retinoic acid
Reproduction
o Retinol
o For the production of sperm
Measurement


Deficiency  plasma retinol bleow 10ug/dl (0.3umol/l)
?????
Toxicity



Since Vit A may be stored in liver  possible to develop toic condiciton when very high consumption (10 times
than normal intake)
Vit A intoxication is less likely with large intakes of carotene  bcs the conversion is limited
o But since it is pigmented  yellowing of skin  due to deposition of carotene in subcutaneous fat
Hypervitaminosis A
o Increased intracranial pressure
 Headached
 Blur vision
 Vomit
 Lack of muscular coordination
o
o
 Abnormal liver function
 Pain in weight-beaing bone & joints
Inhibit excess vit D effect
 on renal calcification
 in general, antagonized the Ca response to Vit D
 excess vit D  reduce retinol bound to erythrocyte membrane
teratogenic (Any agent that can disturb the development of an embryo or fetus)
 cause CNS
 cranio-facial
 cardiovascular
 other defects

** contraindicated in pregnancy 怀孕禁忌
T4- Vitamin D
Introduction



vitamin D (calciferol) =the term referring to 2 mol
o Ergocalciferol (D2)  plant source
 Ergosterol (fat found in plant) + calciferol
 Most common form= D2 (ergocalciferol)
 Easier to produce as supplement
 Easily found in diet
o Cholecalciferol (D3)  animal source
 Cholesterol (found in animal)
 Most effective form of vit D
 Produced in skin
Both types are equivalent in the effect of prevention of rickets
Dietary D2, D3  biologically inactive
o 2 Activation (hydroxylation) steps:
 Hydroxylation in liver
 Add a hydroxyl grp to D2 / D3  calcidiol (25-hydroxyvitamin D)
o Not fully activated
 Hydroxylation in kidney
 Add another hydroxyl grp to calcitriol (1,25-dihydroxyvitamin D)
o Fully activated form
Food sources


Animal source: (D3)
o Fatty fish
o Fish Liver oils
o Beef liver
o Cheese
o Egg yolk
Plants source (D2)
o Mushroom



 To increase D2 in them  treat with UV radiation
Fortified food: (with D3, but sometimes with D2)
o Milk
o Plant milk
o Cereal
Supplement
o Mostly D3
Vit D in food are fairly stable, not prone to losses via cooking, storage or processing
nomenclature & structure


D vitamins listed are a family of seco steroids that differ only in structures of their side chains
o Seco-steroid  bcs normally steroid has 4 ring, vit D only has 4, but one of them is broken
Pathway of formation of Vit D3 (precursor  activated form)
o UVB (ultraviolet B) radiation on 7-dehydrocholesterol (found in skin) convert to previtamin D3 
unstable preD3 stabilized by rearranging via thermal isomerization  stable vit D3 diffuse from skin
to blood
o
o
o
o
o
7-dehydrocholesterol
 Synthesized In skin’s sebaceous glands  secrete onto skin’s surface
 Activated by UV  previtamin D3
 UV trigger the opening of B-ring  only then this comp is considered as vitamin D
related compound  to have vitamin activity
Previtamin D
 Only have 2 double bonds

To be a real vit D vitamin activity
 Hydroxyl grp at C-3 + presence of 3 conjugated double bonds
Activation (blue)  hydroxylation
 Liver
 25
o 2-5X potent than D3
 Kidney
 1,25
o 5-10X potent than D3
 24,25
o Inactive form
o May be excreted by kidney into urine
Requirement

Active vit D is given in IU
o




1 IU uses D3 as reference standard
 1g cotton seed oil solution of D3 contains 10mg of the vitamin
Elder need more vit D
o Skin conversion and production of Vit D reduce
Sufficient amounts of vitamin D are thought to be obtainable by exposure to sunlight for about 5 to 15 minutes
between about 10 a.m. and 3 p.m.
Other factors:
o Season of the weather
o Altitude
o Skin complexion
 Melanin block YVB rays
o Disease lead to fat-malabsorption
 Crohn’s disease
 Pancreatitis
 Liver disease
RNI:
o
o
o
o
o
metabolism
 Absorption
o
o
o
o
o
o
Absorbed passively with food fat & dependent on presence of bile salts
No digestion needed
Absorbed with LCFA packed in chylomicrons  lymphatic system  blood
Primarily:
 Jejunum
 Ileum
Form:
 Hydroxylated
 Unhydroxylated
Renal disease & excessive amt of sun blocker / lack sunlight exposure
 Synthesis of D3 impaired
 Depend more on the dietary vit D3  intestine uptake of active form of Vit D
 Transport
o
o
o
o
o
Mainly by
 Chylomicrons (main source from diet)
 DMP (mainly when vit D is processed in the body)
 Vit D from chylomicrons is transferred to DMP (vitamin D-binding protein)
o All forms of Vit D can be carried by this protein
To:
 Adipose tissue, muscle, other tissue  remaining back to liver
 Obese ppl tend to store more vit D  low vit D in obese need higher doses to reach appropriate
serum conc than normal weight
Metabolism in liver
 Hydroxylate vit D to 25-OH D calcidiol by Cytochrome P-450 hyroxylase
 Mostly secreted into blood by DMP
 Little remain in liver  blood is the largest major storage site of calcidiol
 ½ life = 12 days -3 weeks
 ** circulating serum calcidiol conc  reflect vit D status
Storage form:
 25 hydroxyl D3 calcidiol
 In blood, some maybe taken up by other tissue like adipose for storage
 Accumulate in liver, kidneys, lungs
 Kidney uptake of calcidiol is stimulated by PTH  convert to active form calcitriol 
released to blood for other tissue use
o PTH secreted when serum Ca is low
o High serum Ca & P inhibit calcitrol synthesis
Calcitriol
 X accumulates
 This active form X stored but found in almost all cell & tissue type
 High calcitriol may stimulate the inactivation
 Upregulate 24-hydroxylase  form 24,25- (OH)2 D from calcidiol  excrete in feces
Function

Their mechanism involve genomic & nongenomic
o
Calcitriol increase absorption of Ca due to:
o Calcitriol after syn in kidney, travel to enterocyte, get into their nucleus, upregulate specific genes
encoding for protein involved in Ca uptake & transport  synthesis of Calbindin (calcium-binding
protein)
o Elicit a change in membrane permeability to Ca at the brush border
 Induce expression of Ca-ATPases & Ca channel transporters in enterocytes

Induce uptake of phosphate & Mg by brush border of intestine
o Increase protein binding to Ca & phosphate (similar mechanism as for Ca)
o The Ca binding protein unintentionally bind with Mg (with lower affinity)

Bone mineralization
o When PTH & calcitriol present in low conc The deposition of minerals into the bone (Ca)
o When high conc  promote resorption of Ca & P from bone to restabilize serum Ca
Deficiency:
o Rickets in children


o
Characterized:
 Seizure
 Growth retard
 Failure of bone mineralization
o Enlarge of bone at wrisk, ankle, knees
 The cartilage gorw and enlarge without replacement by bone matrix
and minerals
 Reduce calcification of bone  skeletal deformities  bone pain, muscle weakness
Adults osteomalacia
 Low vit D and calcium conc  increase PTH  increase bone mineral resorption
 The bone matrix is preserve, but remineralization is impaired  soft bone
 Bone pain , muscle weakness
 Vit D help to regulate muscle contractility by regulating Ca uptake and secretion
Ricket vs Osteomalacia vs Osteoporosis

Osteoporosis

o Bone is thin & brittle due to too little mass
o But the mineral & composition is normal
o Deficient of Ca
Osteomalacia
o Total mass normal
o But lack of mineralization
o Deficient of Vit D
Measurement


Main indicator:
o 25-hydroxyvitamin D (calcidiol) in serum
o normal value= 27.5 nmol/L
o longer circulating ½ life = 15days
calcitriol  not goof indicator
toxicity


storage capacity of liver for D precursor is much less than its capacity for A
o hard to get toxicity frm natural source
o supplement  risk
symptom:
o excess calcification not only of bone, but also in soft tissue
 kidney, heart, lungs, blood vessel
o hypercalcemia, hyperphosphate  renal dysfunction
o hypercalciuria
o urinary Ca stone
o anorexia
o nausea
o vomiting
o thirst
o polyuria
o muscular weakness
o joint pain
o disorientation
o death
T4- Vitamin E
Introduction



8 naturally occurring forms of Vit E syn by plants (vitamers)
Common structure:
o Phenolic functional group on chromane ring (head)
o Phytyl side chain (tail)
8 vitamers Divide into 2 classes
o Tocopherols (4)
 Have saturated side chain with 16 carbons
o Tocotrienols (4)

 Have unsaturated side chain with 16 carbons
Each clasees has 4 vitmaers
o Each dif in the number & location of methyl frp on the chromanol rings
o They cant be interconverted
o Alpha-tocopherol most biological active
Food sources





Found in many dif food both animal and plant, but more amt in plant
Found mostly in frm plant  Esp oil of plant
o Wheat germ oil
o Palm oil (tocotrienol> alpha tocopherol)
Animal source
o Primarily alpha-tocopherol
o Higher-fat meat
o Less good source of vit E
Susceptible to process
o What germ is removed in milling  white flour
o Oxidized when exposed to air, light, heat
 Roasting nuts reduce vit E content
Alpha-tocopherol  highest biological activity

nomenclature & structure

Most active naturally occurring form= alpha-tocopherol



o Alpha-tocotrienol  highest activity among the tocotrienol
o Alpha-tocopherol  highest activity among all 8 forms of vit E
Consist of:
o Double ring structure
o Side chain at C2 (differential tocopherol / tocotrienol)
 Tocopherol= X double bond (saturated)
 Tocotrienol = have double bond (unsaturated)
o 3 methyl grp (5, 7, 8) <at least 1 methyl grp>
  dif no. or place of methyl grp differentiate the tocopherol / tocotrienol
 Tocopherol:

o
Alpha = 3
o
o
o
Beta= 2 (5, 8)
Gamma =2 (7,8)
Delta= 1 (8)
o

** all forms have
 1 OH- at C6
 1 CH3- at C8
Isomers/ synthetic Vit E
o Commercially available products as acetate / succinate ester
 ** ester X usually occur in nature
o Uncommon to have vit E deficiency than other vit  may be due to mal function of Vit E
production/absorption (fat- malabsorption)
o

tocopheryl acid succinate is more effective  0.89
Requirement



IU of vit E activity  activity of 1 mg of alpha-tocopherol acetate = reference standard
o Though a-tocopherol is 36% more active than acetate  still use acetate as reference
o Bcs: readily available as a standard comparison
Hard to determine the requirement
o Vit E = antioxidant  the requirement may be affected by the antioxidant present in our body
 Eg: Selenium , vit C
o The PUFA level in body
 Increase PUFA increase the need of vit E
RNI?
Metabolism
 Absorption
o
o
o
o
o
Free tocepherols  no need digestion
Esterified tocotrienol or supplement  need digestion
 Pancreatic esterase and bile-dependent mucosal esterase  hydrolyze tocotrienols & syn ester
alpha-tocophenol
 lymphatic system  lipoprotein complex
Enhance by presence of fat in intestine
 Esp SF
 Decrease by PUFA
Most at jejunum & ileum

Via diffusion across enterocyte membrane
 Transport
o
o
o
o
o
o
Absorbed vit E  incorporated into chylomicrons  liver
 B4 entering liver, tocopherl can be transferred among other lipoprotein HDL, LDL
 LDL posses highest con tog tocopherol
Intracellular transport
 Alpha-tocopherol-binding protein alphaTTP
 Synthesize in liver
 Found in
 hepatic cytosol
 heart
 transfer alpha-tocopherol into VLDL  distribute to other tissue  reaching into ather tissue
 ATTP are needed to bind ti vit E for intracellular transport  into membrane
 deficient of ATTP  vitamin E deficiency
Reservoirs:
 Adipose tissue (over 90%)
 Increase with increase dosage of vit E
 Other tissue relatively stable conc
 Muscle
 Liver
 If diet Vit E not enough, use the reservoir  until deplete
 Rate of depletion with dietary inadequacy varies considerably
o Affected by other antioxidant
Found in all cells
 Mostly in
 Adrenal cell
 Testicular cell
Increase intake of b-carotene & Vit c  protect a-tocopherol depletion
Increase PUFA  increase need for antioxidant
Function
o
Antioxidant (main)
o Function is shared with  affect requirement of Vit E frm diet
 b-carotene,
 ascorbic acid
 regenerate vit E following its oxidation
 Se-dependent glutathione peroxidase
 Cu-Mn-Mg dependent superoxide dismutase
o ** the one with higher conc may cover/compensate the deficiency effect of the other one
o ** beauty product  add vit E as antioxidant




Maintaining membrane integrity of body cells
o Prevent oxidation of unsaturated FA of phospholids of membranes
 Tissue with cell membranes more susceptible to oxidation
 Lungs
 Brain
 RBC
o Expose to high conc of O2
Correct damaging effect of Free radicals on DNA
o In steroid hormone syntheses
o Spermatogenesis  infertility  pherol= birth
Protect RBC
o The enzyme glutathione peroxidase (selenoenzyme)  activate by vit E acting as free radical scavenger
 protect hemoglobin & cell membrane frm oxidation by free radical
Prevent oxidation of LDL
o Prevent CVD
Measurement

Use a-tocopherol as indicator (have 8 members)
Toxicity



Least toxic vitamin
High doses acts as antagonist to vit A,D,K
Symptom: (>900mg/kg of the diet)
o Headache
o Nausea
o Muscle weakness
o Double vision
o G disturbance
o Increase bleeding
 Due to anti-platelet effect
Deficiency

Cause
o Premature infant
o Fat malabsorption disorder

 Cystic fibrosis
o Genetic ATTP deficiency
Consequence
o Infertility in men
 Vit E imp in production of sperm
o
T4- Vitamin K
Introduction


3 classes: (2natural + 1synthetic)
o K1 (phylloquinone)
 Found in plants
o K2 (menaquinones)
 Synthesis by intestinal bacteria
o K3
 Synthetic form
 Will be converted into K2 by microbiota
Normally, newborn is injected with vit K bcs the intestine is sterile  X syn vit K  needed for normal blood clot
 prevent VKDb (bleeding)= hemorrhage disease
Source:


K1  major source of dietary vit K in human diet
Plant:
o Green leafy vege?
Nomenclature & Structure:

Structure give vit K activity:
o 2-methyl-1,4- naphthoquinone


Structure requirement:
o A methyl grp at C2
o Side chain at C3
 Can be vary in length 
 Affect vitamin activity
o If K1 & K2 have same length of side chain  similar activity
o There is an optimal length for optimal activity
 20 carbon side chain
 Any length greater / shorter than 20 will have less vit K activity
 Affect vitamin potency
o Potency vs activity:
o


Drug A is more potent than B
o At the same response magnitude, A is needed in less
dose than B
Drug B is more efficacy than A



o
o
o B has a higher maximum response magnitude than A
Activity= efficacy= the max effect to be achieved by a specific
concentration
Higher potency, need lesser amt to exert the effect

The higher the comparative potency, the more potent it is, the
lesser amt needed to give the effect.
Benzene ring must be unsubstituted
Can exist in cis or trans configuration
 All trans-phylloquinone = naturally occurring form
 Mixture of cis & trans forms:
 Synthetic phylloquinone
Requirement:


Since our microbiota can synthesis vit K , hard to set a requirement and is variable
USA suggest: 30-100ug/d
o Esp for long-term antibiotic treatment
Absorption：




Most of the fat-sol vit are absorbed befor reaching large intestine, except for vit K
o Bcs production of vit K is at LI, specifically the colon ??
K1 & K2  use transport process
K3  passive diffusion
Site:
o K1  small intestine (from diet, most nutrients absorbed here)
o K2  ?
o K3  in large intestine bcs need to be ocnvered by microbiota to K2 first
Function

Blood coagulation
o Promote synthesis of GLA in the liver (G-carboxyglutamic acid)
 GLA  essential part for prothrombin (coagulation factor II) and other coagulation factors (VII,
IX, X)
 With no vit K  no GLA  not factor II, vII, IX, X
 ?????
o Involves 4 phases that must interdigitate if a clot is to be formed
 Formation of thromboplastin
 Activation of thromboplastin
o
 Formation of thrombin
 Formation of fibrin
Involve many substances / coagulations factors



4 out of 13, associated with vitamin K
Osteocalcin
o Carboxylated protein that contain Gla found in bone matrix
 Since Gla  need vit K for synthesis
o Synthesis in bone tissue (osteoblast)
 Highest during rapid growth
 ???????
Deficiency



Rare  as body can produce
Only due to secondary vit K deficiency  delayed / prolonged clotting time
o Biliary disease
 diseases affecting the bile ducts, gallbladder and other structures involved in the production and
transportation of bile  fat malabsorption  affect vit K absorption
o Long-term broad spectrum antibiotic therapy
 Kill microbiota
o Anticoagulant therapy using warfarin
 Prevent blood clot in blood vessel
 Warfarin
 is one of the anticoagulants
o Interfere the function of vit K  = anti-vitamin K
o Vit K affected X produce that 4 coagulation factors  X blood coagulation
 Used as rodenticide
o Colorless, odorless, tasteless  put in food let the rat eat  hemorrhage 
excessive bleeding
Symptoms:
o Numerous bruises (subcutaneous hemorrhage to injury)
Toxicity:


Large intake of naturally occurring vit K X toxic
Supplements of vit K  X be taken with warfarin
T4ii- water-soluble vitamin




Cannot stored in body, need to consume enough amt daily
Exp:
o Thiamine
o Riboflavin
o Niacin
o Pantothenic acid
o Pyridoxin
o Biotin
o Folic acid
o Cyanocobalamin
Though they are classified under vit B  dif chemical and structures  dif function
All 8 vit B always present in the same food
Thiamin B1

Structure:
o Consist of:
 Pyrimidine ring
 Thiazole moiety
 Contain a sulfur atome
o Linked by a methylene bridge (CH2)
Food source:


Animal:
o Phosphorylated form
 95% Thiamin diphosphate (TDP) = thiamin pyrophosphate (TPP)
 5% thiamin monophosphate (TMP) & thiamin triphosphate (TTP)
o Meat (esp pork)
Plant:
o In free nonphosphorylated form
o Legumes, grain (whole, fortidied, enriched)
o Yeast


o Wheat germ
o Soy milk
Supplement:
o Thiamin hydrochloride
o Thiamin mononitrate salt
Process susceptibility
o Destroyed primarily at methylene bridge by
 Alkaline
 Heat
o Cooing thiamin-rich food in water promote loss of thiamin
Nomenclature & structure




A pure vit B1 form is unstable
Can present in 3 dif form in body:
Thiamine pyrophosphate (TPP)
o 80%  exist in cells
Requirement:
o
o
o
Thiamine requirement are related to energy metabolism
Factor :
o Age
o Caloric intake
o Carbs intake
o Body weight
o Presence of infection
o
Men > women
 Due to body size and energy needs
Metabolism：





Absorbed by
o Passive diffusion
 With high thiamin intake, passive diffusion pre-dominate
o a specific active transport mechanism
 Thiamin transporter ThTr1 & ThTr2
 ** alcohol inhibit intestinal expression of ThT2  inhibit thiamin absorption
o Most rapid in duodenum
Phosphorylated form:
o Need to hydrolyze the phosphate from TDP, TMP, TTP to free thiamin b4 absorbed into enterocyte
o In enterocyte
 Thiamin may be phosphorylated back
o Only TMP / free form can cross the cell membrane
Absorption rate:
o High
o Affected by antithiamin factors  destroy thiamin
 Thiaminase in raw fish
 Reduced with cooking
 Polyhydroxyphenols
 Tannic
 Caffeic aicd
o Thiamin destruction is prevented by reducing agent
 Vit C
 Citric acid
Transport
o In plasma
 Free form bound to albumin
 TMP
 90% of thiamine in blood is present within RBC as TDP (formed within the cell)
Liver:
o Most free thiamin is taken up by liver  phospholyrated to TDP= TPP (coenzyme form)
o 80% OF TOTAL Thiamin in body is TDP= TPP
o

 Thiamin X present in their free form in our body
Body X store the vit  need daily supply
Function:

Coenzyme role in energy transformation
o As TPP= TDP
o Not directly act in the function, but needed for the activity to run
o Coenzyme for oxidative decarboxylation of:  generate energy (ATP)
 Carbohydrate metabolism
 Pyruvate  acetyl CoA
o Happens b4 the citric acid cycle
 In kreb cycle
o Alpha-ketoglutarate  succinyl CoA
 Fat metabolism
 BCAA
o Coenzyme of BCKDH
 Alcohol metabolism
 The same enzyme convert pyruvate  acetyl CoA also convert acetaldehyde  acetyl
CoA
Deficiency:

Due to malabsorption & poor diet intake
o Beri beri = weakness
 Types:
 Dry
o Predominantly in adult
o Due to low thiamin intake + high carb intake
o Characterize:
 Muscle weakness & wasting , esp lower extremities
 Peripheral neuropathy
 Affect nerve conduction in limbs  paralyze
 Wet
o More extensive cardiovascular system involvement than dry


o Edema of heart failure
o Digestive disorders
Acute/Mixed
o Mostly in infant
o Characterize:
 Anorexia
 Vomiting
 Lactic acidosis
 Cant conver pyruvate to acetyle-CoA pyruvate onlyc an be
converted into lactic acid
 Neural & cardiac symptoms

 Clinical manifestation varies depend upon the severity of deprivation
Due to chronic alcoholic
o Why?
 Reduce vitamin intake due to reduce food consumption
 Increase requirement due to liver damage
 Main site of thiamin phosphorylation  TDP=TPP
o Wernicke-Korsakoff syndrome (dry beri beri)
 Due to their poor diet
 Characteristic
 Wernicke’s encephalopathy:
o Confusion
o Low lvl of consciousness
o Poor coordination
 Korsakoff’s psychosis
o Happen when Wenicke is not treated
o Brain damage  Memory loss
o
Mechanism:
 Malnutrition frm poor diet
 Decrease ability of duodenum absorption of vit B
 Result in Impaired Krebs’s cycle  XATP production  brain X enough ATP  brain damage
 Enzyme involved:
o PDH
o Alpha-KGDH
Measurement

Red cell Transketolase
o Thiamine is the cofactor of this enzyme
o Low transketolase activity  low thiamin
Toxicity



Dietary/oral intake B1  rare
Most  injection of B1
3g/d  symptom
o Headache
o Irritability
o Insomnia
o Weakness & tachycardia
Riboflavin B2



Name:
o Ribo = ribose-like side chain
o Flavin = yellow color
Structure:
o Flavin mol
 Isoalloxazine ring
o Sugar alcohol side chain
 Ribitol side chain
Forms:
o 2 coenzyme derivatives
 FMN (flavin mononucleoide)
 FAD (flavine adenine dinucleotide)
Food source




Source:
o Animal source: (most!)
 Dairy product !!
 Milk, meat, eggs
o Plant
 Wheat germ
 Fortified cereal/ flour
o Human production
 Microbiota can produce small amt of b2  but not enough to meet dietary need
Form in food
o Free
o Protein-bound
o In the form of coenzyme FMN, FAD
Used immediately & X stored in body
o Excess amt are excreted in urine
o Bright yellow color urine!
Source in diet is unstable
o Exposed to UV light
 Up to 70% will be lost frm milk during 4 hr exposure to sunlight
 That’s why packaging of milk is not transparent glass anymore
o But resist heat, oxidation, acid
Nomenclature & Structure



C7 & 8 must be substituted with more than just a hydrogen
Amine grp at C3  must be unattached
A ribityl group at C10
o Most imp that contribute to vit B activity

o
Solubility
o Can be enhanced when solvent pH increase (alkaline)
 When pH increase, the stability towards UV & heat will decrease/ too acidic  deactivated
easily
 The ribityl grp is lost during deactivation  no vit activity at all
o

** Riboflavin must be protected from light and acid
Requirement



There is almost no riboflavin reserve  daily intake is essential
Imp for pregnancy!
o B2 deficiency may lead to congenital birth defect
 Heart defect & limbs deformation
Absorption




All 3 sides of SI can absorb
o Max absorption in jejunum of SI
o Significant uptake by duodenum & ileum
B2 found in food maybe
o Attach to protein
 Must be freed to be absorbed by:
 HCL , gastic & intestinal enzyme hydrolysis of protein
o Phosphorylated form of coenzyme FAD, FMN
 Must be dephosphorylated in intestinal lumen  free to absorb

 Pyrophosphatase cleave FMN , FAD
 Alkaline phosphatase  liberate vit frm its coenzyme form
By active carrier
o Energy & Na dependent
o RFT2
Factor:
o Bile facilitate absorption
 Small amt of vitamin circulate via enterohepatic system
o Alcohol impair B2 digestion & absorption

Enter enterocyte before enter portal blood
o Rephosphorylated to reform FMN, FAD  bound to albumin and transport in plasma
 The initial phosphorylation reaction is Zn-dependent
o

Circulate in blood bound to plasma protein, albumin
Function

coenzymes that involve oxidation-reduction

o
o

Flavin act as oxidizing agent
 Ability to accept a pair of hydrogen atom


Most are oxidase/ reductase
Many of these enzyme involved in
 mitochondrial respiration
 ATP synthesis
 Mitochondrial citric acid cycle
 They are also called= flavoproteins
 Eg:
 Succinate dyhydrogenase its activity = biomarker of riboflavin intake sufficiency
 Acyl-CoA dehydrogenases  fatty acid oxidation
 Hence riboflavin is essentially needed in regulation of metabolism
Contained in flavoproteins
o Involved in many oxidation-reduction reactions in many metabolic pathway
 Serve as intermediate electron carrier with NADH
Deficiency



=Ariboflavinosis
Rarely occur
Symptom:
o Poor growth
o Poor appetite
o Skin lesion


Outside of the lips = cheilosis
Corner of mouth = angular stomatitis
Measurement



Hard to
Urinary excretion
Measurement of erythrocyte glutathione reductase activity coefficient (EGRA)
o FAD is co-factor for EGR reflect long-term riboflavin status
o Activity coefficient:
 Represent a ratio of enzyme’s activity with FAD to the enzyme’s activity without FAD
o When addition of FAD stimulate enzyme activity to generate an AC of 1.3-1.4  low riboflavin status
 > 1.4 = deficiency
o When FAD added, AC <1.3  acceptable
Niacin B3
Introduction:

Discovered due to pellagra 糙皮病
o




characterized by dermatitis, diarrhea, and mental disturbance, and is often linked to overdependence
on corn as a staple food.
Niacin is a generic term for
o Nicotinamide
o nicotinic acid
o
2 forms in food  different physiological properties
o Both are very stable in dry form
o But amide
 More soluble than acid
 Most supplement is amide form
 in solution  readily hydrolyzed to acid form
Abt 50% of niacin in body is syn frm AA tryptophan
Work in body as coenzyme with more than 400 enzyme dependent on it for various reactions
Source:


Widely distributed in human food supply
o Esp:
 Best= fish & meat
 Whole grain cereal
 Bread
 Milk
 Egg
 Vege that are richly colored
Form in food
o Animal:
o nicotinamide
o
nicotinamide nucleotide
 NAD (nicotinamide adenine dinucleotide)
 NADP (nicotinamide adenine dinucleotide phosphate)

Plant:
 Nicotinic acid
We cant get B3 from corn
o bcs it is bound covalently to the protein (niacinogens) or complex carbs (niacytin)
 Reduce availability
o But with some process, the B3 is freed from the protein
 Chemical treatment with bases like lime water
 Exposure to gastric acid
 Exp: tortilla
Endogenous Synthesis
o In liver, from tryptophan
o Is an imp contribution to the niacin needs of the body
o


o

Need Fe & PLP (vit B6)
 Deficiency of these nutrient impair niacin synthesis

Nomenclature & structure




2 forms:
o Nicotinic acid
o Nicotinamide
 More soluble in water > nicotinic acid
Very stable in dry from
o But amide form is readily hydrolyzed to acid in solution
Mainly appear as coenzyme forms in body
o X appear as free form
Important structure:
o Pyridine ring
o Carbon 3 is substituted with side chain
 Beta-carboxylic acid  nicotinic acid
 Amide  nicotinamide
o Open sites at pyridine carbons 2-6
Requirement:




Hard to give an exact level bcs is affected by protein level as well
Low protein diet increases the need for niacin
o Tryptophan can be converted into niacin
Niacin equivalent= 1mg niacin= 60mg tryptophan
RNI
o
Metabolism




NAD & NADP need digestion to nicotinamide before absorbed
o
Both forms of niacin are absorbed into enterocyte by
o Simple diffusion
 High conc, completely by passive diffusion
o Facilitated diffusion
 ** B1 & B2 are absorbed by active transport
Vitamin circulates in blood in its free form
o Mostly nicotinamide free form
 Some bound to plasma protein
o Free form may diffuse across cell membrane  uptake by tissue
 But some tissue need carrier for nicotinic acid transport
 Kidney tubule
 RBS
 Need energy
 brain
o If not converted into NAD+ / NADP+ (coenzymes) will be metabolized further and excreted in the
urine
In tissue:
o Amide / acid are used to syn NAD  NADP
 NAD usually found as its oxidized form NAD+
 NADP  mainly reduced form  NADPH
Function:

NAD, NADP are coenzyme of primarily dehydrogenases
o Act as H donor or E- acceptors
o
o
o

Nicotinamide is incorporated into these coenzyme
Involved in many oxidoreductase reaction
 Glycolysis
 FA metabolism
 Tissue respiration
 Detoxification
 Folate coenzyme synthesis
Used as drug in clinical as lipid-lowering drug
o Nicotinic acid
o Niacin inhibit TG synthesis, lowering serum TG
o Doses of 1-2g/day are used in the treatment of hyperTG & hyperchol
Deficiency:


Vitamin deficiency scale great concern
o Quite a big concern compared to other vit B
Pellagra
o Pelle= skin, afra= rough
 4 Ds – dermatitis, dementia, diarrhea, death
o Dermatitis
 Skin exposed to sun  inflamed  progress to pigmentation, cracking, peeling
 Casal’s collar
o
o

Diarrhea
 Often accompanied by inflamed tongue
Dementia
 Symptoms range frm mild confusion & disorientation  mania
Measurement



Metabolites NMN (N’-methylnicotinamide) * N’-methyl-2-pyridone-5-carboxamide
o Need 24hr urine collection
o NMN to creatinine ratio = <1.5mmol/mol  deficiency
o This metabolite is directly proportional to niacin level in body
Concentration of NAD in red cell
o NAD= coenzyme form of niacin
Fasting plasma tryptophan
Toxicity:



Chronic administration of 3g/day
o Theoretically, niacin is to produce ATP can boost up energy level
 But if you take more X make your body stronger
o It’s hard to get toxicity as it can be excreted in urine
Too much  vasodilatory side effect
Symptom:
o Headache
o Heartburn
o Nausea
o Hives
o Fatigue
o Sore throat
o Dry hair
o Inability to focus the eyes
o
skin tautness 紧绷
Pantothenic acid (B5)  CoA
Introduction:



panto = everywhere
consist of
o 2 component:
 beta-alanine
 pantoic acid
o joined by: peptide bond
o
used to form a part of coenzyme A
o A = acetylation
o
source



widely distributed in food
o but highly processed food X contain the vitamin
excellent source:
o organ meat !!!
o mushrooms
o avocado
o broccoli
o whole grains
 when it is processed to produce refined grain (white rice, flour)  no B5
 B5 is found at the outer layer of the whole grain
Food process:
o Destroyed easily by heating & freezing

Nomenclature & structure


Only has 1 chemical compound (others got many)
Form
o Free acid
o Supplement
 Calcium salt
 Unstable pale yellow oil
 Or commercially available as white stable, crystalline Ca / Na salt


When dry, salt is stable to air & light but is hygroscopic 吸湿的
Readily destroyed by
o Heat
 Hydrolytic cleavage of the mol produce
 Beta- alanine
 2,4-dihydroxy-3,3-dimethyl butyrate
o alkaline/acid pH
Requirement

gut bacteria can produce B5 but not enough to meet daily need
o hence info is X available to derive recommended intake

Metabolism


Form in food:
o Bound as component of CoA
 CoA need to be hydrolyzed  free B5
o Free
 Passive diffusion
 When high amt
 Facilitated diffusion
 When Low amt intake
 SMVT (sodium-dependent multivitamin transporter)
o SHARE with biotin, lipoic acid
Transport
o Diffuse into blood travel in 2 forms  travel to liver and other cell
 Free
 Within RBC (most)
o

Tissue high in B5 (used for CoA)
 Liver
 Adrenal gland
 Kidney
 Brain
 heart
Large doses of B5 / after its release from CoA rapidly excreted in the urine
Function
o
Part of coenzyme A (CoA)
o Imp in citric acid cycle = kreb cycle
o Essential for reaction involve carbs/ lipid metabolism
o B5 is the backbone of CoA, but not serve at CoA active site
 Still imp la cuz no B5, no CoA
 no need memorize
o
Toxicity


Not been described in human as single entity
Large dose  GI symptom
Deficiency:



If it occurs, accompanied by other deficiency disorder as well
Increase need
o Alcoholism
o DM
o IBS
Symptom
o Burning feet syndrome
 Numbness of the toes & sensation of burning in feet
Pyridoxine B6

3 naturally occurring forms: (inter-convertable)
1. Pyridoxine (alcohol) PN

 Plant source
2. Pyridoxal (aldehyde) PL
3. Pyridoxamine (amine) PM
 Last 2 
 Animal source
 more potent precursors for coenzymes pyridoxal phosphate (PLP) & pyridoxamine
phosphate (PMP)
o To have the activity, need to be phosphate
Each has 5’-phosphat derivative

Food source:



Plant
1. Form: pyridoxine PN
2. Stablest form
3. Its; phosphorylated form PNP  found exclusively in all plant food
4. Some in conjugated form pyridoxine-glucoside
animal
1. PD, PM, their phosphorylated derivatives
2. Not so prevalent than plants
Food process:
1. Fairy stable with cooking
2. Destroyed by:
 Prolonged heating (sterilizing & canning)
 Milling & refining of grain

Nomenclature & Structure




B6 Is the generic descriptor for all methyl-3,5- dihydroxymethyl pryridine derivatives
Imp structure for B6 activity
1. Phosphorylated at 5-hydroxymethyl grp
 Hence, need to be added with phosphate to have the coenzyme activity
2. C4 substituent must be convertible to aldehyde form
 Pyridoxal = aldehyde form dy
 Need 1 more step to activate
o Add 1 phosphate at C5
 Pyridoxine & pyridoxamine= not aldehyde form but can be interconverted
 Need 2 steps:
o Change C4  aldehyde
o Add 1 phosphate at C5
Pyridoxine HCl
1. Synthetic form of B6
2. Stable to light & heat in acid solution
 But unstable in neutral & alkaline solution
Pyridoxal
1. Aldehyde form is much less stable
2. Instability to heat  major concern in food process
3. Moreover, most food rich in B6 is neutral  slightly alkaline
 Make them even more unstable
4. Esp concern: infant formula
 Infant formula needs to undergo autoclave to kill food borne pathogens
Requirement

B6 is imp in AA metabolism requirement are linked to protein intake
Metabolism







Phosphorylated must be dephosphorylated
1. Done by Zn-dependent alkaline phosphatase & intestinal phosphatase at brush border
2.  PN, PL, PM
Pyridoxin glycoside  hydrolyze to be freed
Absorption
1. Preferably free form
2. Phosphorylated form
 If ingestion of high amt of phosphorylated from
Uptake by passive diffusion X active transport  special (jejunum, ileum)
1. B1,B2, B5 active transport
In enterocyte
1. Some may be phosphorylated to PNP, PMP, PLP
Carried by RBC to all cells  tightly bound to protein (hemoglobin & albumin)
Significant amt of vit B6 may be found in liver, brain, spleen, kidney, heart but not stored
In liver:


Unphos  phos
PNP, PMP  PLP (main vitamer)
1. By FMN-dependent oxidase
 Need riboflavin

In blood:


PLP is the main form of the vitamin found in systemin blood
1. Mostly bound to albumin
Since only unphos vitamers may be taken up by tissue, PLP typically hydrolyzed prior to cellular uptake
Function
PLP coenzyme
 In reaction whose substrates contain nitrogen  amino acid
1. transamination
 Produce keto acid & synthesis of NEAA
2. Decarboxylation (removal of COO-)
 Yield bioactive amines
 Neurotransmitter (NE, E, serotonin, dopamine, GABA)
 Histamine
3. Porphyrin synthesis
 Coenzyme in the 1st step in synthesis of heme
 Hemaglobin
4. Niacin synthesis
 From tryptophan
 PLP-dependent reaction
5. Cysteine synthesis
 Cystathionine synthase & lyase ate PLP-dependent enzyme
 PLP for transulfhydration
 Homocysteine  cysteine
Glycogen degradation
 PLP is needed for glycogen phosphorylase to catabolize glycogen  glucose-1-PO4
 Hence most PLP in muscle is bound to glycogen phosphorylase
Deficiency


Target:
1. Infant with severe heat treatment infant milk
 Form PLP=lysine  little vitamin activity
 Sign:
 Seborrheic rash on face, neck, shoulder, butt
 Esp: seizure, convulsion
2. Elderly
 Poor intake of vit B6
 Accelerate hydrolysis of PLP & oxidation of PL
3. Alcoholics
 Impair conversion of PN, PM  PLP
 Acetaldehyde enhance coenzyme degradation
Other sign
1. Weakness, fatigue
2. Cheilosis, glossitis
3. Sideroblastic (Microcytic, hypochromic) anemia
 Due to impaired heme synthesis
4. Impair niacin synthesis from tryptophan
5. Inhibit metabolism of homocysteine
 Hyperhomocysteinemia
Toxicity:



Loss of sensation in feet
Peripheral neuropathy
Daily dose:
1. Not exceeding 10 mg/d
measurement


Plasma conc of pyridoxal phosphate PLP
1. Normal : above 30nmol/L
Total vitamin B6
Biotin B7 skin



Found out due to egg white injury
1. Eating raw wgg white causes hair loss, dermatitis
2. Found out biotin can cure this
8 isomers
1. Only D-biotin is biologically active
Source
1. Diet
2. Gut microbiota syn in colon
Food source:




Found in every living cell in minute amt
2 forms:
1. bound
 amino acid lysine  biocytin
 Protein bound
 Glycoprotein bound
o Avidin in raw egg white
 Heat labile  can be destroyed with cooking  no adverse effect on
biotin absorption
o Irreversibly bound to biotin  prevent absorption
 Need to hydrolyze frm the form to be freed to absorb
2. Amide
 Free form
 Natural form
Rich source
1. Organ meat
2. Egg yolk
3. Brewer’s yeast
4. Royal jelly
Other
1. Soy flour/ soybean
2. Ocen fish
3. Whole grain
4. Human milk

Nomenclature & structure:


Name: cis-hexahydro-2-oxo-1H-thieno (3,4-d)imidazole-4-pentanoic acid
Imp structure:
1. 2 ring:
 Ureido ring
 Thiophene ring
2. Side chain
 Valeric acid

Requirement


Difficult to determine
1. Can be form by gut
3-7mg is consider adequate

Metabolism

Can exist in food in 2 form
1. protein bound
 need to be digested
 proteolysis by pepsin & intestinal proteases  free biotin, biotinyl peptide, biocytin
 biocytin hydrolyzed by biotinidase  lysine + biotin
 genetic disorder of biotinidase deficiency  biotin deficiency
 Not all will be hydrolyzed
 less than 50% of plant origin (low conversion rate)
 animal origin more readily available > plant



2. Free
 Absorbed readily
Absorption
1. Form:
 Free
 Some biocytin, peptide-bound
2. Mechanism:
 facilitated diffusion
 when high dose (pharmacologic foses as needed with some genetic disorder)
 carrier mediated
 SMVT
o Shared with pantothenic acid & lipoic acid
In blood
1. travel to liver  bound to liver plasma membrane receptor (SMVT)
2. form:
 unbound , free (~80%)
 bound to plasma protein
storage:
1. stored in small quantities in muscle, liver, brain
Function
Coenzyme of several carboxylic enzyme
 biotin is covalently bound to some types of carboxylases
 Involved in nutrients metabolism
1. Gluoconeogenesis
2. Fatty acid synthesis
3. Amino acid catabolism
4. Protein synthesis: keratin
 Found mainly in mitochondria and cytoplasm
1.
2. Serves as mobile carboxyl carrier
 When it is attached to enzymes that catalyze carboxyl grp transfer
Bound covalently to histone (DNA-binding proteins)
 Bound to histone tail  regulate gene expression
1. Biotinylation of histone tail  histone uncoil  expressed
 Maintain DNA structure
Hair, skin, nail
 Biotin improve body’s keratin infrastructure
Deficiency




Extremely rare in normal population
1. Can be syn by intestinal bac
Cause
1. Long-term eating raw egg
 reversible
2. Defective biotinidase enzyme
3. Alcoholism
 Impair biotin absorption
Symptom:
1. Dermatitis
2. Skin rash
3. Hair loss, alopecia
4. Developmental delay
5. Seizure
6. Conjunctivitis
7. Visual & auditory loss
Complication
1. Reproductive failure
2. Impair growth & development of fetus
Measurement:


Available in whole blood or urine
Normal range:
1. Whole blood: 0.22-0.75 ug/ml
Toxicity


No report
Cause diarrhea due to large doses
Other:

Certain supplement high in biotin is stated:
1. Can promote the health of hair, nails, skin
2. Cause biotin can improve body’s keratin infrastructure
 Beyond this, no further evidence liao  hence not conclusion
3. But it can maintain the health of hair,nail,skin, not really improving
B9 Folic Acid



Discovery:
1. Folate + vit B12  cure megaloblastic anemia
Folic acid
1. Tho it is synthetic form , not it is more available for absorption and stable
2. 85% absorption rate
Folate
1. Natural form
2. Commonly found in many food
3. Folate folium= leaf
Food source



Both plant and animal origin
Exp:
1. Meat
 liver
2. Frutis
3. Vege
 Esp asparagus
4. Dru beans
5. Peas
6. Nuts
7. Whole grain cereal
Food process:
1. Heat destroy folate
 Raw > cooked
2. Oxidation, UV

Nomeclature & Structure:


Important Structure for vitamin activity:
1. Pteroic acid
a. Pterin ring
b. PABA (para-aminobenzoic acid)
2. Glutamate
Derivative of folic acid
o Has dif subgrp at N5 & N10
o
Requirement


Human X produce own folate hence essential & highly needed
o Required in daily diet
o Though is available in many foods, but the absorption rate is 50% only
 Unless folic acid fortified la
Women contemplating pregnancy (trying/ aldy pregnant)
o Need increase intake 2X for folate
o
Metabolism



absorption
o Folate natural in food
 50% bioavailability
 Polyglutamate form
 Up to 9 glutamic acid residues attached to PABA
 Mostly= 5-methyl tetrahydrofolate (5-MTHF)
 need to be digested to monoglutamate b4 absorbed
 By carboxypeptidase
o Zinc dependent
o Affected by alcohol
 Both Zn & alcohol impair polyglutamate absorption
o Folic acid
 Monoglutamate
 100% absorption
o Absorbed form:
 Monoglutamate form
 5-methyl THF
o Carrier mediated
 2 types of specific Folate binding protein
 Low affinity
o At brush border membrane of absorptive cell
 High affinity
o PCFT (proton-coupled folate transporter)
o Mostly at duodenum & upper jejunum brush border cells
o Absorption is reduced in alkaline, improved in acidic cond.
within enterocyte:
o Folic acid & folate  reduced to dihydrofolate (DHF)  reduced to THF (tetrahydrofolate)
o
circulation
o as monoglutamate form (free form)



 Folate
 5-methyl THF
 10-formyl THF
o Bound in RBC
 RBC X take up folate from the circulation, but the amt of folate Is bound to RBC during
erythropoiesis  RBC folate conc represent longer term folate status than plasma (2-3month)
Uptake by tissue:
o Carrier mediated
 RFC reduced folate carrier
 PCFT proton-coupled folate transporter
In liver:
o Glutamate is added  polyglutamate form of THF  storage form
excretion
o not used  excrete in urine as
 pteroylglutamic acid
 5-methyl-pteroylglutamic acid,
 10-formyltetrahydrofolate,
 acetamidobenzoylglutamate.
o Very little in feces
Function:

Coenzyme in one-carbon transfer (methyl group)
o Activation needed for activity
 Need to be activated to bcm  Tetrahydrofolate acid THF used as coenzyme
o DNA & RNA synthesis:
 Imp in purine & pyrimidine & glycine syntheses
o Other
 Methionine

Genetic disorder:

MTHFR
o Coenzyme form of folate are interconverable
o Except 5-methyl THF cannot be directly converted back to 5, 10-methylene THF
 MTHFR enzyme are needed to convert 5,10-methylene THF to 5-methyl THF
 Lack of MTHFFR  reduce 5-methyl THF --. Reduce remethylation of homocysteine to form
methionine
 But we can get 5-methyl THF naturally from diet, but not folic acid
Interaction with other nutrients

Vitamin B12
o Without vit B12, methyl group from 5-methyl THF cannot be removed trapped
 = methyl-folate trapped
o Even enough folate intake  X not in the form to be used for DNA synthesis
 Including:
 10-formyl THF  purine
 5,10- methylene THF  thymidylate
Deficiency

Megaloblastic macrocytic anemia
o RBC is
 Lesser
 Larger


 Immature
 Shorter lifespan
o Due to disrupt DNA synthesis & cell dividion
 Folate needed for purine & thymidylate synthesis

dermatitis, impaired growth
o Common in chronic alcoholics
 Alcohol prevent folate absorption
Imp for development of embryo
o Deficiency in pregnant women prior  affect early stage of embryonic development
 lead to spina bifida & other neural tube defect
 A gap in the spine
 Not fully enclosed
Measurement


Recent intake is assessed by serum folate
o Measure blood sample
o Normal level:
 2-11 ug/L
Cellular status by red cell folate
o Normal level
 150-700 ug/L
Toxicity

Hardly as can be excreted by urine
Cyanocobalamin B12



Discover due to it can cure pernicious anemia
Complex mol that contain cobalt
Commercial form
o Cyanocobalamin
 Can be converted into natural form
Source




Found primarily from animal origin products
Plant
o fortified food la
o contaminated with microbes from manure
Unstable to
o UV light
o Acid
o Metal (Fe, Cu)
Stable to:
o Light
o Heat
o Oxidation
o
Nomenclature & Structure

Imp structure:
o Cobalt-centered corrin ring
 Consist of
 4 reduced pyrrole rings
 In the ring center  Cobalt
o At 3+ state
o Can form up to 6 bonds
 Tightly bound to 4 pyrrole N atoms
 can bond a nucleotide & a small ligand below & above the ring respectively
o
Requirement



Daily requirements is very small
o Normal turnover rate = 2.5ug/day
 Hence recommendation for adult is close to turnover rate or 2 ug/day
o Body gut microbiota can synthesis but not enough for need
Strict Vegetarian & vegan  take note of B12 intake since X take in animal products
Pregnancy:
o Increase need for B12 for growth & development of infant

Need for DNA & RNA synthesis

Metabolism (4 binding protein)



Vit B12 in food is bound to protein
o B12 is in complex form of protein
In stomach
o Pepsin + Acid  dissociate B12 frm protein
o B12 bind to another protein heptocorrin (called R protein, produced in salivary gland)
 To protect B12 frm acidic pH in stomach & bacterial use
In duodenum
o R protein degraded by pancreatic enzyme + alkaline environment free B12
 In acidic environment  vit B12 is prefereably bind to R protein > IF
o






B12 bind to another protein , intrinsic factor (produced in parenetic cell of stomach but escape
digestion)
 IF is imp for absorption by intestinal cell
 No IF no absorption
In ileum
o IF + B12  complex bind to IF receptor = cubilin take up by intestinal cell
 Active transport
 Defect of cubilin  B12 malabsorption
In enterocyte:
o Vit B12 released from IF complex
o Transported to portal blood  bind to mainly transcobalamin 2 (produced by ileum mucosal cell)
 Or other TC1, TC3
Large intestine
o Small absorption happen here
o Mostly are those produced by gut microbiota
o Passive transport
Trqnsport in blood
o Transcobalamin II
 Genetic disorder SNP
 Reduce TC ability to bind with Vit B12 for distribution
 Consequence:
o Low serum vit B12
o High serum homocysteine  risk factor of heart disease
o Haptocorrin-like protein
Storage: ** unlike other water sol vit, can be stored in body for long time (even years)
o Stored form: Adenosyl cobalamin
o Site
 Liver
 Kidney
 Heart

 Spleen
 Brain
Malabsorption
o Destruction of gastric parietal cell  IF  pernicious anemia
o Inability to release food-bound cobalamin to bind to IF  food-cobalamin malabsorption
 Normally in older ppl
o Acidic intestine pH  unable release B12 from R-protein
Function

2 enzymatic reaction in 2 dif form
o methylcobalamin
 methionine synthesis
o adenosylcobalamin
 convert L-methylmalonyl- CoA to succinyl-CoA in mitochondira
1. Imp for myelination of nerve
a. Nerve exon is covered by myelin sheath  speed up impulse transportation
2. Recycling of folate coenzyme
a. Reconvert folate into active form
3. Synthesis of methionine from homocysteine
a. One of the way to measure B12 lvl  measure lvl of homocysteine
i. If B12 less  high homocysteine
1. Accumulate homocysteine due to no B12 convert homo back to methionine
4. Coenzyme of various enzyme
a.
Deficiency

Has body storage  takes months to develop

Megaloblastic anemia 巨幼红细胞性贫血
o
o
o

Pernicious anemia 恶性贫血
o
o
o


Larger size of RBC , lesser amt
Affect DNA synthesis  affect RBC synthesis (RBC rapid turnover)
Cause:
 Lack of dietary B12 intake or folate
 Hence it is reversible / irreversible depending on the cause
A type of megaloblastic anemia which body X absorb vitamin B12 due to lack of IF In stomach secretion
Caused by:
 Lack of IF
 Vit B12 is not absorbed
 Can be reversible with intravenous B12
Treatment
 Intramuscular injection of vit B12 or high oral dose  induce passive diffusion
Peripheral neuropathy
o Due to insufficient SAM for methylation reaction of myelin
o
o
o

Nerve damage with numbness
 Numbness will spread as the cond getting more serious
 Cant hold things
 Cant walk/ stand  need wheel chair as X walk anymore
Tingling in the hands & legs
Irreversible disorder
 Once nerve cell damage, it X be undone anymore
o
Vulnerable population:
o Strict vegetarian
 Since B12 only found naturally in animal product
 Should include B12- fortified food or B12 supplement
 In the free form
 But still need the other 3 proteins for absorption
 ** if its pregnant more careful!
o Lack of IF
 Pernicious anemia
 Normally due to autoimmune disease attaching GIT cells  affect IF secretion
 Even high dose of B12 supplement X solve
o Inadequate stomach acid
 Due to insufficient released of bicarbonate to SI (achlorhydria)
 X release B12 frm food
 10-30% of adult over the age of 50 have difficulty absorbing vit B12
 Recommend to eat B12 supplement that is aldy in free form, no need acid to free them
o Intestinal surgeries / digestive disorder that cause malabsorption
 Eg: bariatric surgery
 Some may affect stomach where IF made or
 Ileum where B12 is absorbed
o Impaired intestinal fucntion
 Esp ileum
 eG:
 celiac disease
 crohn’s disease
 decrease absorptive surface
o competition
 ppl with parasitic infection
 tapework
 parasite uses vitamin
 causes:
 prolonged use of H2 blockers & proton pump inhibitors
o use to tread GERD
o due to bacterial overgrowth

due to alkaline intestinal environment due to medication diminish acid
production
Measurement


Blood B12
o Not the best way to determine deficiency
 Not as confirmative test
o Affect by diet greatly
o Normal B12 level in blood nay not means normal cell lvl/ activity
 May not be taken up by cells due to some defect
Better marker:
o Blood level of methylmalonic acid
 A protein breakdown product
o Blood level of homocysteine
o Their value may increase with B12 deficiency
Toxicity


No specific toxic effect
o Large dose may casue GI symptom like diarrhea
No adverse effects have been associated with excess B12 intake from food & supplement in healthy individual
Vitamin C



ascorbic acid
o exist in 2 isomer
 L & D But only L- ascorbic acid is biologically active in human
Naturally in some food
Unlike most animal, human X syn vit C due to lack of enzyme = L-gulonolactone oxidase
o From glucose/ galactose
Source:


Destroyed:
o Heat
o Light
o Oxidation
Alkaline solution  but stable in acidic solution
 Cooking and storage may reduce vit C
o Fe & Cu
 Ingest large amt of Fe & CU with Vit C may oxidative destruct vit C in GI tract
Supplement:
o Free ascorbic aicd
o Calcium ascorbate
o Sodiul ascorbate
o Ascorbyl palmitate
o

Requirement:




Widely vary di dif countries due to dif definition
o Eg:
 Based on the conc of Vit c in WBC
 Based on Vit C lvl in the body that X show any symptom due to Vit C deficiency
Smoking increase vit C requirement
o Increase vit C turnover
o Estimated value: 80mg/d
Pregnant & lactating women
o +20, +20mg respectively
o Why?
 When we prepping infant formula, tend to use high temp  destroy the vit C
 Hence one of the good sources of vit C for infant is breastmilk
 Cow milk also very low in vit C  so not so recommended lo
 For development of infant
 To produce collagen  needed in muscle tendon…
Stressed / traumatized persons
o Increase vit C requirement
 Serve as antioxidant to neutralized harmful ROS
Nomenclature & Structure:

Ascorbic vs dehydroascorbic
o Natural form found in diet
 L- ascorbic acid
 2,3-didehydro-lthreo- hexano-1,4-lactone.
 Dehydroascorbic acid
 oxidized form
o But the distribution is dif
 Ascorbic  80% (more prevalent)
 Dehydroascorbic  20%
o Interchangeable:
 Ascorbic  lose 2 hydrogens  dehydroascorbic
 ** they are readily donate/ receive hydrogen
 Dehydroascorbic acid can be reduced to ascorbic acid with Hydrogens provided by GSH (reduced
form of glutathione)

Both are biological active
Imp structure for vitamin activity
 2,3- enediol (green)
 2 -OH adjacent to a double bond
 Dehydroascorbic don’t have  hence ascorbic higer activity than dehydroas
 6 carbon lactone
Exist in d- & L- form
o Only L has biological activity
o
o



o
Stable in dry form but once dissolved in water, it is easily oxidized
pH:
o Stable in solution in acidic environment (pH below 4)
 Hence fruits contain vit C is normally acidic
o In high pH degraded easily
 Esp heated, exposed to air, in contact with Fe, Cu salts
Metabolism:


Does not require digestion
Ascorbic acid
o (but not dehydroascorbic acid) can be absorbed throughout SI
o Via Active transport system = SVCT
 Sodium vitamin C cotransporter
 Found in intestine one is mainly type 1
 Other than transporting AA into cell, also transport 2 Na into the cell
o Hence SVCT can only function in the presence of Na in extracellular space
o No sodium, no influx of Vit C
 Indirectly active transport
o To ensure Na conc is high in extracellular space for use  use sodiumpotassium pump that use 1ATP to transport 3Na out , 2K in
o Hence we can find many Na/K pump in ileum for the absorption of vit C
o
But SVCT itself X use ATP, but its Na/K needs
o





o
Enterocyte vit C conc higher than capillary
 Passive diffusion out enterocyte to blood
Dehydroascorbic
o Absorbed by GLUT
o Once absorbed, rapidly reduced back to ascorbic with the help of GSH
Absorption rate:
o 70-90%
o Decrease with increase intake of vit C
 `** if the conc of vit C too high in supplement  slow down absorption  excrete in urine
 SVCT X take up vit C continuously  got a limit
Transport in circulation
o Free form
o No need carrier
Storage:
o Not store in the body
o But higher in some organ than in plasma (5-100times)

They need vit C for their function


o
Brain
o
Vit C serve as cofactor for enzyme to convert dopamine  noepinephrine
Why?
 Due to more SVCT 1/ 2
 Due to ascorbic acid recycling
o Asc can be dehydrolyzed/ oxidation into DHA (dehydroascorbic acid)
 DHA can be transported into cell with GLUT1/ 3 (glucose-transporter) 
passive diffusion due to conc gradient!
 Their main function is to transport glucose into cell as passive
diffusion
o Hence almost all the cell got GLUT for energy
o GLUT 1 all tissue
 Higher in RBC, blood-brain barrier
o GLUT 3  mainly CNS, brain
 In the cell:
 DHA  reduced back to Asc by adding 2 hydrogen atoms
 DHA conc decrease, Asc conc increase
o Due to conc gradient, DHA outside cell passively
diffused into the cell again
o This is how the cell regulate the Asc recycling


Metabolites:  excrete in urine
 Ascorbate-2-sulfate




Oxalic acid
Ascorbate
Dehydroascorbate
2,3-diektogulonic acids
Function:

Basis of their biological function
o Oxidation & reduction of ascorbic acid
o Further oxidation (irreversible) diketogulonic aicd = biologically inactive
 No 6-carbon lactone
 No enediol
o






Powerful reducing agent (antioxidant)
Help protect other antioxidant
o Reconvert vit E
o
Synthesis of collagen
o Imp to stop bleeding
 Need collagen to close up the wound
 Hence vit C deficiency  scurvy as part of prolyl hydroxylases & lysyl hydroxylases
 Vit C function as a reductant to reduce the Fe from ferric to ferrous in these enzymes
o Vit C role in hydroxylation reaction related to Fe cofactor
The hydroxylation of dopamine to neurotransmitter noradrenaline
Production of carnitine
o TRANSPORT fat into mitochondria for beta-oxidation  ATP production
o Vit C also act as reductant of Fe from Fe3+  ferrous of an hydroxylase
Enhancement of Fe absorption
o Take fruit juice tgt with meals
o Non-heme iron



Metabolism of drugs
o Imp coenzyme in cytochrome P450 oxidase
Activation of peptide hormones
This function is due to its coenzyme role in certain enzyme responsible in the function above
o Except antioxidant la  it’s the function of vit C itself
o
Cold vs vit c



Vit c enhance IS by
o Promoting chemotaxis
o Proliferation of some immune cells like macrophages & lymphocytes
o Increase activity of NK cell
o Destroy histamine
Ingest high doses of vit C X prevent common cold or reduce symptom
Regular vit C use appear to modestly reduce duration of symptom by 3-13% in adult
Deficiency



Poor wound healing
o  scurvy = Bleeding gums, skin hemorrhage
Affect energy production
o Carnitine affect
Fe-deficiency anemia
o Due to decreased absorption of non-heme iron
o Esp vegetarian la
o


 Petechiae= red skin discoloration due to ruptured small blood vessels
Vulnerable population for Vit C inadequacy:
o Vit C inadequacy:
 Can also occur with Intake that fall below RDA but are abv the amt required to prevent overt
deficiency (ard 10mg/day)
o Smokers/ second hand smoker
 Lower plasma & WBC vit C levels than nonsmoker
o Infants
 Infant formula treated with high temp
 Cow milk less vit C
 Hence feed them with breastmilk
 Lactating mother need increase vit C to transfer to milk
Measurement


Plasma
o <11mol/L ->17mmol/L
WBC
o Adequate  > 2.8pmol/106 cells
o Better reflect body stores
Toxicity




Vit C X prevent infection
o But it will make your body stronger and faster recovery
Obtaining the RDA or slightly higher may be protective against certain disease states
Toxicity very rare
o Bcs the absorption of vit C is dose dependent
High lvl (10g/day)  kidney oxalate stone
o One of the metabolite of vit C is oxalate
 May be eliminated in urine
 But high lvl of oxalate  react with calcium to form calcium oxalate  stone
 Mild cases
o Just crystal
 Severe
o Many crystal form stone
Whitening effect of vit C?


May inhibit the oxidation of melanin
But intravenous is better than dietary vit c la
o
Cant absorb that much of vit C
T5- mineral

Macro mineral vs trace mineral
Criteria for essentiality of minerals & trace elements:
1.
2.
3.
4.
5.
Present in healthy tissues
Concentration must be relatively constant
Deficiency induces specific biochemical changes
Supplementation corrects the abnormalities
Deficiency changes are accompanied by equivalent abnormalities
Macrominerals: (greater than 100mg per day)
1.
2.
3.
4.
5.
6.
Calcium
Phosphorus
Magnesium
Sodium
Potassium
Chlorine
Trace Minerals: (1mg-100 mg per day)
1.
2.
3.
4.
5.
Iron
Zinc
Copper
Selenium
Iodine
Ultramineral (less than 1 mg per day)
Calcium

5th most abundant element int eh body
o 1.4g/kg
 99% deposited as HA (hydroxyapatite) Ca5(PO4)3OH
 in bone & teeth
 For rigidity
 1%
 Intra & extra-cellular fluid
o Ionic form Ca2+
o Bone:
 150mg Ca/g bone
o

Soft tissue：
 Liver, muscle, brain
 Less than 35 ug Ca/g tissue
Ca plasma level Controlled by 3 hormones:
o Parathyroid hormone PTH
o 1,25 dihydroxycholecalciferol (calcitriol)
o Calcitonin


Other factor affecting Ca mobilization & deposition
o Age
o Diet
o Hormonal status
o Physiological state
Bone Ca homeostasis
o If mobilization exceed deposition  bone weak  osteoporosis  break easily
o Relate to bone strength
 Ca mobilization mostly happens in bones & plasma,
 seldomly in teeth!
Food source:



Poor source:
o Spinach, rhubarb,  oxalic acid
Better absorption in animal source than plant
o Ca in milk and dairy food more readily absorbed than in plants
 Due to anti-nutrients
 Phytate
o In cereals
 Oxalates and tannins
o Leafy green vegetables
Ca is absorbed better in the free form
o These anti-nutrients may bind to the Ca  reduce the bioavailability

Ca in milk may also bind to other protein = lactalbumin
 But this X affect the absorption
 But if consume with plant food with those anti-nutrients  affect Ca absorption
 Cereal + milk
Enhancer of Ca absorption
o Vitamin C
 Vit C reduce Ca to the reduced form that is more bioavailable
o Phosphorus
 Normally food with high Ca is high in P  no need purposely find food high in P to pair with Ca
Supplement:
o Calcium citrate
 Good for those with limiting gastric acid production (older ppl)
 Can be ingested without food
o Calcium carbonate
o Take note:
 Generally absorbed better with food
 Absorption higher consumed in less than 500mg
o



Requirement

More focus on elderly ppl on Ca requirement
o They need more Ca
o reasons:
 Elderly tend to have lower physical activity
 Low Ca retention in the body
o PA influences Ca turnover through increase Ca retention
 Elderly has lower expression of TRPV6 & calbindin
 Post-menopause women lower estrogen
 Reduce Ca absorption from the diet
o Oestrogen can increase calcium absorption directly and indirectly by stimulating
1-α hydroxylaseactivity in the kidney.
 Hence elderly more risk to osteoporosis as bone is the main site for Ca in homeostasis

o
Other
 Lactation:
 Need more Ca  mammary gland needs high Ca to produce breast milk  nutrients for
baby
 Growth
 Need more Ca for bone development
Metabolism:




Ca naturally in food & supplement  insoluble salt
o Can be solubilized  free Ca2+ from Ca salt
o But solubilization X ensure better absorption
 Free Ca may bind to other dietary constituent, limiting bioavailability
 But Ca bind with milk lactose  improves Ca solubility  absorption increase
 This effect more pronounce in infant > adult
Not all consumed Ca is absorbed
o Unlike Na, potassium, chloride
o Reason:
 Presence of anti-nutrients
 Food source
 Mixture of food consumed
 Physiological status of individual
Absorption main site:
o Small intestine  duodenum to ileum
o Only small amt 10% in colon
2 mechanisms for Ca absorption:
a. Paracellular transport (diffusion)
i. Through the tight junction between mucosal cells
ii. Passive Diffusion  no need energy
1. From high conc to low conc
iii.
b. Transcellular transport
i. Active transport  need atp
ii. = vit D-dependent transport
1. Calcitriol
iii. When Ca intake low – moderate
iv. Steps:
1. Ca diffuse across the brush border down its thermodynamic gradient into the cell as free
unbound Ca++
a. Required the transport protein= TRPV6 (transient Receptor Potential Vanilloid
subfamily member 6) no need atp at this point
i. Vit D-dependent
2. Bind to intracellular protein= calbindin (also known as D9k)
a. Transport Ca across cytosol
b. Vit D-dependent
c. Carry Ca to the other protein  released Ca into plasma
3. Vitamin-D-dependent Ca-ATPases pump
a. Release Ca into plasmaa
b. This need atp
c. This is a co-transport
i. Ca release + Mg take into the cell
1. 2+ in, 2+ out
2. To maintain the ion balance

3.
Ca form in transport in blood
o Most 50% of the blood Ca is free form= ionized Ca2+
 100mg/L (2.5mmol/L)

 May have small decline in older age (10%)
 due to age-related decline in total calcium-binidng capacity of serum protein
o The other 45% Protein-bound calcium
 Prealbumin, albumin
o Small 5% Ca  complexed Ca
 Bind to phosphorus, sulfate, citrate
o It’s imp if we wanna measure plasma Ca  as the value is reflecting the free Ca, not including those
bound to protein/ complex
Homeostasis of Ca:
o Extracellular Ca conc regulation
 Regulated by
 Active vitamin D / calcitriol
o renal tubule
 increase reabsorption
o intestine
 increase absorption
o mechanism
 increase expression of TPRV6 & calbindin
 Calcitonin
o Totally opposite effect of PTH & calcitriol
o Also syn by thyroid gland (parafollicular cells)
o Help prevent Ca toxicity + make sure bone have enough Ca
 Inhibit osteoclast-mediated bone resorption
 Inhibit activation of Vit D
 Inhibit renal Ca conservation
 Parathyroid hormone
o Low level of Ca in blood will stimulate the release of PTH on the thyroid gland
o Pth ACTS ON
 Kidney
 Increase calcitriol synthesis  act on renal tubule  Increase
Ca reabsorption  reduce Ca loss
 Bone
 Stimulate the release of Ca frm bone to blood
 Inhibit collagen synthesis by osteoblast stimulate their
proliferation & differentiatin into osteoclast (bone-breaking cell)
 Osteoclast release protease & acid  resorb/degrade bone 
release Ca to blood

Nutrients interaction  inhibition of absorption
Divalent Cation (Zn, Mg)
 Compete for intestinal absorption esp an excess of one in GI tract
Unabsorbed dietary fatty acids
 Form insoluble Ca soup
 Cannot be absorbed  excrete in feces
Drugs
 Proton pump inhibitor
o Used to treat GERD
o insufficient product of Gastric acid
Function
1. Bone mineralization
o 99% of total body Ca is found in bones & teeth
o Ca is part of mineral comlplex deposited on an organic matrix comprised primarily of type I collagen
o Hardness is enhanced by presence of fluoride
2. Cell signaling
o Though less than 1% of total body Ca serves in cell signaling system  but the flux of Ca from one
compartment to another is vital in metabolic regulation
 For communication between cells + between organelles inside the cells
o The flux is facilitated by intracellular Ca-binding protein = calmodulin
3. Cell death
o In normal state  cell only allow fixed amt of Ca come into the cell
o If the cell is injured  Ca balance is disrupted  active energy-driven export of Ca will be interrupt Ca
continue flow into the mitochondria –> raise ionic conc of mitochondrial matrix  mitochondrial
dysfunction
o Ca influx into the cytosol + nucleus  cell die
o Very imp if it happens in heart cell
 Heart muscle cell die  heart failure!
4. Muscle contraction
o In muscle cell, special endoplasmic reticulum= sarcoplasmic reticulum= calcium storage site  imp for
muscle contraction
o
Deficiency



In early adulthood
o  stunted growth
o Failure to achieve peak bone mass
 A risk factor for osteoporosis in later life
Children
o Poor Ca absorption due to vit D deficiency  rickets
Causes
o Kidney failure
o Reproduction system disorder
 Hormonal imbalance  affect Ca absorption and retention
Toxicity



Accumulation in blood & tissues due to dietary excess is unknown
o Bcs Ca level is controlled tightly by homeostatic control of hormone
Excessive Antacid tablets & Ca supplement
o Excessive intake of Ca & alkali  MAS milk alkali syndrome
 MAS is reported at Ca carbonate intake >= 4g/d or more
o Reversible once stop these tablets
o Symptoms:
 Nausea, vomiting, dry mouth, confusion, lethargy
May cause kidney damage
o Calcium may bind to oxalate Form crystal

Measurement



Normal plasma range for Ca= 2.15-2.55mmol/L
Usually X affected by dietary insufficiency
o Bcs plasma Ca level is tightly controlled
o Hence not good to reflect the Ca status in bone
Bone mineral concentration can be measured by
o Neutron activation analysis
o DEXA dual X-ray absorptiometry
Phosphorus：



80-85% is found with Ca in hydroxyapatite (HA) in the bone
Other form in body
o Phosphate PO4o Rarely free phosphorus
o present in every cells
Ca & P are essential minerals that usually considered tgt bcs the formation of bone & uptake of Ca for this
purpose is closely tied to an optimal ratio of Ca:P of 1:2 – 2:1
Food source:



Food source high in P is also high in Ca
Present in
o all natural food
o In many addictive
o Soft drink  phosphoric acid
Absorption is atd 60% of intake
o Reduced by non-starch polysaccharides
Metabolism




Form:
o Organic bounded phosphorus
 Nned to be digested  release inorganic Phosphate
 By phospholipase
 Can be upregulated by calcitriol
 But X free all bound form
o Eg: X phytic acid-bound P
2 absorption mechanism:
o Readily absorbed in the free form
1. Paracellular absorption
2. Transcellular transport
 Active saturable sodium-dependent mechanism
 Sodium-phosphate Co-transporter
o 2NA + 1phosphate  transport into the cell tgt at the same time
o Need ATP
o
Aluminum, magnesium (as hydroxides), and calcium (as carbonate or acetate) are common
components of antacids and for years were given in pharmacological doses to bind dietary
phosphate in people with hyperphosphatemia (high blood phosphorus concentrations) caused by
kidney disease.
Reabsorption
o At kidney 
 85% proximal convoluted tubule
 10% loop of Henle
 3% distal convoluted tubule

2% collecting duct

Renal phosphate conservation



main mechanism for P homeostasis
Enhance
o • Vitamin D/ calcitriol
 Stimulate phosphate intestinal absorption
o • Glucocorticoids
o • Growth hormone
Inhibit
o • Oestrogen
o • Thyroid hormones
o • Parathyroid hormones
 Stimulate excretion of P In urine > (override) Stimulate resorption of P from bone
 Net effect: reduce plasma P
o • Elevated plasma Ca levels
Function:




Skeletal rigidity tgt with Ca  hydroxyapatite
Energy metaboslim
o Form ATP  phosphate bonds in ADP
Constituent of phospholipid and membrane
Constituent of nucleic acid
Deficiency:


Hardly happen as dietary deficiency as it found in every type of food unless have some disease
Fanconi Syndrome
o Kidney disorder
 Wont be able to control the release of these substances (phosphate) into urine


 Hence urine may have high ………
 Lead to phosphate deficiency
o To correct this phosphate deficiency phosphate supplement  to prevent skeletal bone disorder
(need both Ca and P for bone health HA)
Consequence:
o Bone pain & poor skeletal growth & mineralization
o Lack of HA for deposition in the bone matrix
Other factor
o Phytate form insoluble salt with Ca, Mg, Fe rendering these minerals unavailable for absorption
Toxicity:


Generally high intake are balanced by high excretion in urine
o But may be disrupted in renal patients
Excess P can cause
o Diarrhea
o Hardening of organs & soft tissue
Measurement:


Serum total phosphate levels are measured.
The normal adult range is 0.7–1.5 mmol/l.
Magnesium:




Both vegetables and meats are good sources of Mg
o milk and milk products are relatively poor sources of this mineral.
Mg stabilizes mammalian membranes and in plants.
o ionically bound in the centre of the chlorophyll molecule.
Mg is a cofactor in almost all phosphorylation reactions involving ATP.
universality of its presence in the food supply low deficiency states if consuming a variety of foods.
Food source:



Spices, nuts and cereals are rich sources of Mg.
Green leafy vegetables such as spinach are also rich in Mg.
Beverages rich in Mg are coffee, tea and cocoa.
Requirement:

Ca is for contraction  Mg for relaxation
o Work antagonistic
o Due to muscle relaxation  imp during pregnancy
 Prevent the uterus to contract too early
o Lactation lady:
 Need more Mg  good source of nutrients for body for growth and teeth?

Metabolism:


Absorption:
o Same as Ca & P
 Mediated by both passive diffusion & active transport
 Paracellular & transcellular
o But Mg for paracellular transport need protein = claudins
o Transcellular need protein = TRPM 6 & 7
o Absorption rate vary from 30-70%
o
o
o
Fatty acid
 Form soap with Mg
Phosphorus
 Form a complex Mg3 (PO4)2  X absorbed
 Both inhibit each other
Calcium
 Mg is needed for Ca absorption




Transport in plasma
o 55% - free ionic form Mg2+
o 33%- protein bound
o 13% complexed with citrate, phosphate, sulfate
Homeostasis
o Renal excretion
Hormone affect Mg metabolism
o PTH
 Increase intestinal Mg absorption
 Reduce renal excretion
 Enhance bone Mg resorption
Function:
Bone integrity
 Bone mineralization
o Tgt with other mineral + phosphate  HPX
o Bone has 50-60% of Mg
 Exchangeable Mg pool to maintain serum Mg
Energy metabolism
 Cofactor for enzyme requiring ATP
 Mg bind to ATP  provide stability
o Replication of DNA
o Synthesis of protein & RNA
Phosphate transferring system
Muscle relaxation
 Magnesium also may mimic or displace calcium from calcium-binding sites, decrease the flux of calcium
across the cell membrane, further inhibit the release of calcium from the sarcoplasmic reticulum in response
to increased influx from extracellular sites, and activate the Ca2+-ATPase pump to decrease intracellular
Ca2+ concentrations.
 Magnesium may compete with calcium for nonspecific binding sites on troponin C and myosin to alter
muscle contraction. Additionally, in smooth muscle, magnesium, if bound to sites that are normally occupied
by calcium, can inhibit contraction.
Membrane stability
 Ca & Mg bind to phospholipid  maintain membrane stability
nerve cell function
Deficiency:


Due to:
o High renal loss
o Malabsorption
 Use of drug
 Diuretics  manage hypertension
Symptom
o Cardiac arrhythmias & cardiac arrest
 Due to Mg has ability to relax
o Calcitriol not so active in promoting intestinal Ca uptake w/o Mg
 Mg is needed to be exchanged for the Ca to pump out of enterocyte
Measurement


Serum Mg
Normal : 0.7-1.0 mmol/L
Toxicity

Occur in renal or adrenal disease
T5ii- Trace Minerals



List:
o Fe
o Zn
o Cu
o Se
o Iodine
Needed in smaller amt , in ug (macro need in milligram)
can further classified into ultra-trace mineral
o excluding Fe, Zn, Cu
o still got a lot la, not only Se, iodine
Iron

essential mineral
o
o


need to make hemoglobin, RBC
 carry oxygen
needed in myoglobin in muscles
 store oxygen in muscle
 Fe in muscle is dif structure with hemoglobin
Form: (2 ionic stage)
o Ferric 3+
 Has to be reduced  to be absorbed & function
 By stomach low pH of gastric juice
 Needed when combine with protein / for storage
o Ferrous 2+
 The only active form that can bind to O2

Food source:


Only can absorbed Fe in free form
o X bind to protein
2 types:
o Heme
 Animal myoglobin  give meat red color
 In ferrous state  binding with O2

Heat/ exposed to O2  ferrous is oxidized to Ferric  red to brownish  not fresh
liao
o Hence manufacture may treat meat with nitrite / CO  bind to the Fe, to
retain it’s ionic state to retain the meat reddish color
o
Non-heme
 Plant
 X in free form
 Inorganic Fe bound to various protein
 Major dietary Fe
 Though we take a lot Fe from plant, the % of absorbed Fe is very low compared with
heme Fe than we can absorbed
 Hence for vegetarian, in order to make sure has enough Fe, or increase the
absorption  take with fruit juice for vit C  enhancer of absorption
o
Non heme more factors affecting the absorption



o
The absorption of non-heme Fe in the presence of meat, fish, seafood
 To investigate whether is protein in the meat that enhance or the type of meat.
 Result:
o Egg absorption enhancer efficiency is << than protein in meat protein
 Hence, not all protein can enhance the absorption
o In the animal meat, there is a factor that encourage the absorption of Fe,
but not identify yet
Requirement:



In 3rd world country  high risk of Fe deficiency due to poor diet
o less meat intake
o rich in whole grain, cereal, legume but only nonheme Fe
o less fruit intake for vit C
menstruating women & growing children  high risk
pregnant  need more Fe for fetus growth
o make more rbc
o tissue growth

metabolism:

absorption:
o mainly in duodenum
o free state of Fe is toxic  hence need close controlled on transport & storage
 by many protein
 transferrin
o transport Fe in plasma



 transport to the sites needed Fe like BM
o temporary holding Fe in intestine mucosal cell
 not the real storage of Fe  just a standby
 if not needed, excreted into the feces
 there is also ferritin in enterocyte  main storage of ferritin
 wont discard Fe stored in ferritin to the feces
 will be stored till they are utilized
Ferritin / hemosiderin
o Long term Storage in a lot of cell
 body X store free Fe
 unused Fe
o site:
 liver, spleen, bone marrow

o
Transport mechanism:
 Dif mechanism for dif Fe  hence not competitive!
1. Heme Fe
 Must be hydrolyzed from the globin portion of hemoglobin & myoglobin b4
absorption
o Done by proteases in stomach & SI
 Protein: HCP-1
o Carry heme Fe into enterocyte
o Found mainly in proximal SI
 In enterocyte:
o Heme (heme-oxygenase)  release ferrous from the heme
1. Non-heme Fe
 Typically bound to componenet of food
o Must be hydrolyzed in the GIT b4 absorbed
1. HCL, proteases  released nonheme Fe, mostly as Fe3+ from the
food component
2. The acidic environment  reduce to Fe2+ (more soluble to be
absorbed ) ** but not all
o If the Fe3+ is not reduced, passed to SI which is more alkaline
1. May complex to produce Fe(OH)3  precipitate  less absorbed


o
o
2. Reduction to Fe2+ by cytochrome B reductase 1 (on the enterocyte
brush border)
 Dcytb is vitamin C dependent
o It also has the ability to reduce Cu2+  Cu+
Protein: DMT-1
o Take up the non heme Fe in ferrous form
 Not in non heme Fe a!!!!
 Can also absorbed other divalent
 Zn, Mn, Cu, nickel, lead
Why less absorption than heme?
o Bcs there is no protein that is specifically take up non-heme frm the gut
o But non-heme iron has to be hydrolyze from the binding protein in the diet
and be reduced to ferrous in order to be absorbed
 This process involved duodenum cytochrome B
 This needs vit C

Enterocyte use:
 Free Fe is toxic  mostly bounded Fe within the cell
 Can be either
 Stored in ferritin temporary
o In ferric form + apoferritin  ferritin
o Increase synthesis in high Fe intake
 Transport to blood by ferroprotein
o oXidation to Fe3+ first by
1. hephaestine (Cu-containig protein)
2. ceruplasmin (Cu-containg preotein)
 ** Cu deficiency reduce their conc  Fe accumulation in
intestine & liver
o Transport by transferrin in ferric state
1. When Fe bind to other protein  ferric state
To liver , BM, muscle, other cells
 Have transferrin receptor  bind and release Fe into Liver
 In the form of
 Hemosiderin
o Lesser storage capacity


Ferritin
o Major storage
Regulation
o Liver produce hepcidin when Fe high

Function



Hemoglobin
o Transport of O2
o Cell respiration
Myoglobin
o O2 storage in muscle
Component of enzyme
o Cytochrome
 Essential for E- transport system in mitochondria
 Transfer of electron due to the change in oxidation state of Fe
o Received e-  reduced to ferrous
o Donate e-  oxidized ot ferric
 Cytochrome P45?  in liver imp for drug metabolism
 Chrome= color  due to heme
Deficiency:


3 stages:
1. Depletion of Fe storage
a. Measured by serum ferritin
i. Ferritin is the main Fe storage
1. Though hemosiderin also store la, but not the main
ii. Fe stores are depleted and serum ferritin levels will fall below 12 μg/l. Other measures
of Fe status will be normal.
2. Fe deficient erythropoiesis
a. Measured by
i. Decreased in transferrin saturation level
ii. Increase erythrocyte protoporphyrin
1. The one that bind with heme to form hemoglobin
2. If heme X form due to lacking of Fe  many protoporhyrin
b. Fe stores are depleted and supply does not meet needs for haemoglobin production. Serum
ferritin levels will be low, serum Fe concentration is low, and transferrin saturation is
3. Actual iron-deficiency anemia
a. Measure by:
i. Depressed hemoglobin
1. Haemoglobin levels <11.5mg/l in women and <13mg/l in men.
2. Red cells are microcytic and hypochromic
3. Mean corpuscular volume MCV < 77fl & mean cell hemoglobin (MCH) < 27pg.
b. Clinical symptom:
i. Pallor
ii. Weakness
iii. Changes in nail
1. Spoon shape when Fe def is very severe
Vulnerable population
o infants and young children (6 months to about 4 years)
 because of the low iron content of milk and other preferred foods, rapid growth rate, and
insufficient body reserves of iron to meet needs beyond about 6 months
o adolescents in their early growth spurt
 because of rapid growth and the needs of expanding red blood cell mass
o females during childbearing years
 because of menstrual iron losses
o pregnant women
 because of their expanding blood volume, the demands of the fetus and placenta, and blood
losses that are incurred in childbirth
Toxicity:

Cause:
o Due to overdose of supplement
o Genetic disease: hemochromatosis
 High lvl of Fe being absorbed
 Fe deposit in liver & heart  cirrhosis, congestive heart failure  death
 Why has higher risk of cancer?
 ROS generation:
Fe is toxic  high lvl of Fe  generate ROS  damage cell  mutation  if
mutated cell not removed  proliferate and form tumordevelop
hepatocellular carcinoma & colon cancer
Cancer cell also need Fe to survive
o



Symptom:
o Bloody diarrhea
Affect other micronutrients absorption
Sodium:



Major extracellular electrolyte
o Circulate as fully dissociated ion due to its +1 charge  fully water sol
Body content
o Male: 52-60 mFq/kg
o Female: 48-55 mEq/kg
Only small amt of Na is involved in Na turnover in body
o (2/3 – 3/4) Mostly are fixed in the bone  mineral apatite
 Can be released when hyponatremia
Food source:


Food addictive
o MSG
o NaCl
 Weight ratio: 40% Na, 60% Cl
 3g of NaCl  1.2g Na, 2.8g Cl (accd to molecular weight ratio)
 1 tsp salt  2300mg sodium
Nearly all food has Na  impossible to have sodium deficiency
o Except pure refined food like pure fat
Requirement




To avoid taking too much  not to avoid deficiency
RNI  based on normal individual has a moderately active lifestyle & lives in temperate environment
o Dif PA & environment & medical condition  affect Na requirement
 High PA/ hot temp  increase Na due to increase sweat loss Na through skin
 Air-con  less Na
Level of serum Na is regulated well in small range  not highly variable
o Hypernatremia > 150 mEq/L
o Hyponatremia < 135 mEq/L
Causes of hyper/ hyponatremia
o
o
Hyponatremia mostly due to disease/ other complication, rarely due to dietary factor, except excess
water intake
Regulation of serum Na




Bcs the range of serum Na is small, need well regulation system
Include regulation of (not only just Na, but other elements as well)
o Na
o K
o Cl
o Water balance
These ions (fully ionized solutes) may affect the osmotic pressure of the system
Mechanism:
o Hormonal



Renin  indirect involve in regulation of Na
o But imp for activation of Angiotensin II  conserved sodium
Hypothalamus:
 Osmoreceptors in anterolateral hypothalamus  sense the changes in Na conc 
activate osmoreceptor  release several hormones
o Na is the most potent ions to stimulate osmoreceptors
 Increase Na 
o ADH by posterior pituitary
1. increase renal water resorption  dilute the Na conc in body
2. X enhance Na excretion, but retain water to dilute Na conc
 Decrease Na + high K 
o Aldosterone by adrenal cortex
1. Increase renal reabsorption of Na ion
o Atrial natriuretic hormone
1. Inhibit ADH
o
o
o
Renin
1. Convert Angiotensin I  II
Angiotensin II
1. Increase Na resorption in kidney
2. Convert to Angiotensin III
 Stimulate aldosterone release  renal resorption of Na

Physical/chemical
Disease due to dysfunction of Na regulation


Diabetes Insipidus
o Absence of ADH
o Body X conserve water  frequent dilute urination & extremely thirsty
o Very high Na in body
o Treated with oral ADH
o Causes:
 Dysfunction of posterior pituitary (tumor…)
Hypertension
o High Na conc  high osmotic pressure
Function
1. Regulation of osmotic pressure/ blood pressure
2. Nerve conduction

To let nerve function properly, there should be a potential difference between inside,, outside of the nerve
 transfer signal
o To maintain this imbalance charge, Na-K pump is very imp!
 Bring in 2+ potassium in, bring out 3+ sodium
 2 potassium ion in, 3 Na ion out.  1 charge dif
 To ensure 2 different:
 Electro chemical gradient
o Imbalance chemical conc
o
Imbalance electric charge
3. Muscle contraction/relaxation



Na/K pump
o is responsible to bring in Ca into the cell
o Bring in Ca, bring out Na out of muscle cell  muscle contract
Na/Ca pump
o Also imp to ensure muscle has enough Ca
Ca pump
o But not involving Na  not discussed

4. Active transport

Mainly  Sodium-potassium pump
o Still got other pump need Na la
Toxicity


Hypertension & Heart disease associated
Symptom:
o Strong emetic
o Excessive oral loads  potentially fatal
o Intravenous  severe & rapid effect
Measurement:


Plasma
Normal range: 135-150 mmol/L
Potassium



Major intracellular electrolyte
o Na is extracellular
o Due to the Na/K pump  bring in 2 K+, bring out 3+ Na
 Hence little K in extracellular fluid (3.5-5 mEq/L)
Healthy male range 42-48 mEq K+/kg
All body K is exchangeable
o Only small amt that is bound irretrievably in bone mineral  X involved in the turnover
Food source:



Milk, milk product, orange juice, avocado, fish, banana
o Myth: banana can prevent muscle cramp due to high level of K
 Bcs the cause of muscle cramp can be due to many reason, X just be prevented by taking
high K though K do have this effect
 It’s just good to be pre-workout to supply simple carb as the immediate fuel
K passes freely from GI  enterocyte  into body
o Most excrete in urine
o Only small amt in feces
Diarrhea
o Short term

o
No need 特地 consume more K to replenish K
Long term
 Need to make sure replacement of K for the loss
 That’s why ask drink 100 plus when diarrhea
Requirement:



Hardly hyponatremia due to dietary factor as almost all food contain K
Increase requirement to give therapeutic effect on hypertension
o High K relax blood vessel  lower bp
o DASH diet 
 reduce NA, increase K  reduce hypertension, risk f heart attack
 fruits & vege  K/Na ratio higher
Function


same as Na  working tgt in Na/K pump
electrophysiology of nerve & muscles
Deficiency:

cause  medical condition
o long term diarrhea  loss of body electrolyte  hypokalemia

o
impact:
o most affected  muscle activity (contraction)
 heart
 bradycardia (low heart beat irregularly)  cardiac arrest
 intestine
 lost in motility
o reduce absorption of nutrients
 brain
 mental depression & confusion
toxicity:


acute intake of supplements exceeding 17.6g / 450mmol
symptom:
o paraesthesia ard the mouth
o tachycardia (fast heart beat)  cardiac arrest
o muscle weakness
measurement:


unreliable
o the plasma conc is replaced by the intracellular K when it is deficient
normal plasma conc = 3.5-5 mmol/L
causes of hypokalemia & hyperkalemia

Chlorine

Involved in
o Osmotic pressure

o Acid-base balance
Normal Cl level
o in plasma:
 100-106 mEq/L

Range very small!!!  变化很小罢了
o

Sweat
 Usually very little
 but can be As much as 40 mEq/L
o intracellular fluid
 veru little ~ 4mEq/L
o intestinal juice
 69-127mEq/L
 HCl gastric juice
o In urine
 Main excretion pathway
o In fece
 Very little
 Bcs in the GI will be reabsorbed and recirculates into the body like Na & K
 Increase excrement in
 Secretory diarrhea
o Your intestine X properly absorb / secrete electrolyte
Passively distributed throughout the body
o Although it is relatively reactive ion chemically
o Cl- move to replace anions lost to cells via other processes
Food source

Table salt
o Tgt with Na
o If excess Na, also excess Cl
 Yet usual plasma Na+ : Cl- ratio = 3:2
 This imbalance due to:
 Passive natur of Cl transfer between water compartments & to the active system that
serves to retain Na+
Requirement

No specific DRV
Function:
1.
2.
3.
4.
Cl is the anion to the cations Na & K
Helps keep the amt of fluid inside & outside the cell in balance
Helps maintain proper blood volume, bp, pH of body fluids
Imp for the function of stomach & RBC
o Stomach:
 Formation of HCl for gastric juice
 For absorption of vit B12
 Kill microbes
o RBC

RBC X carry CO2!!!! It just facilitate the process of transportation bcs 大多数的时间，CO2 在血
液里面 in the form of HCO3-



Chloride shift

CO2 diffuse into RBC  CO2 + H2O – (carbonic anhydrase)  H2CO3 –(dissociated)  H+ +
HCO3 HCO3- will leave RBC  making the RBC to be lack of 1 negative charge
o To balance the charge, Cl- need to come in
At lungs, the Cl- move out, HCO3- move in  convert back to H2CO3  CO2  diffuse out into
lungs
Measurement:


Normal plasma conc:
o 97-107 mmol/L
Abnormal lvl is not diet related
o Due to metabolic reasons related to Na+ & K+ homeostasis
I.
Deficiency hardly can happen due to abundant in food
II.
Tight regulation of body
 Normally if we wanna measure the electrolyte status, we wont just measure one of the
electrolytes, but a lot tgt
 Cl, K, Na, HCO3-
Causes of hypochloremia
o
o
o
o
o
o
Increased extracellular water volume due to trauma and/or cachexia
Vomiting with large loss of gastric HCL
Overuse of diuretics
Overuse of adrenal steroids with retention of Na+
Chronic respiratory acidosis (high CO2, low pH)
Chronic renal disease, renal failure
Cause of hyperchloremia
o
o
o
o
Dehydration
Diabetes insipidus
Brain stem injury
Ureterointestinal anastomoses due to reabsorption of Cl–
Copper

An adult has 80mg of Cu in body
o 40% in muscle
o 15% in liver
o 10% in brain


o 6% in blood
Main function of Cu  cofactor of enzyme
o Incorporated in many metallo-enzyme
Interact with Fe 
o Cu & Fe both are needed for hemoglobin synthesis
 Anemia can due to Cu deficiency
Food source




Not rare  nearly found in all food
Rich in
o Legumes & nuts
 Esp cashew
o Raisin
o Whole grains
o Beef liver
o Shellfish & shrimps
Poor in
o Dairy products
Absorption of Cu
o vary in dif form:
 2 types:
 Cuprous
o Cu+
o Better absorption
 Cupric
o Cu2+
 Hence high lvl of Cu in food X mean it is a good source
 Need to be high in Cu + to be better source
o The presence of other mineral affect absorption
 Zn, vit C, Fe may reduce the Cu absorption
Requirement:


Increase requirement for pregnancy
o Need Cu for
 RBC formation
 Heart
 Bone
 Nervous system
 Blood vessel
Average intake is higher in men than in women
Relationship with Zn


High intake of Zn reduces Cu absorption  High Cu reduce Zn absorption
Why?
o Due to metallothionine (MT)
 Both Zn & Cu can bind to MT
 But
 For Cu:
o Not helping in absorption into the cell
o



o
o
The MT affinity is higher to Cu  bind strongly to form a stable MT-Cu 
stored/ trapped in enterocyte
1. Increase fecal excretion of Cu
Higher MT  higher Cu complex  higher excretion
o
For Zn:
o MT help absorb into enterocyte
o High Zn increase MT expression
Hence
 high Zn  high MT  more Cu excrete
 High Cu  less free MT to bind Zn  more Zn excrete
(A) Normal absorption of zinc (Zn) and copper (Cu) is depicted. Metallothionein (MT) binds both zinc and
copper in the enterocyte but with a higher affinity for copper.
(B) In the setting of zinc supplementation, there is an overexpression of metallothionein, which
preferentially binds copper for excretion into the stool.
Metabolism:

Absorption:
o Mst Cu in food is Cu2+ & bound to organic component like AA
 Need to be freed from AA
 By HCl, pepsin, protease
o Site:
 SI
 limited extent to stomach
o form:
 Cu2+
 Need to be reduced by STEAP reductase  Cu+
 Cu+
 Take up by 2 carrier
o Ctr 1
1. The expression is regulated by Cu intake  high Cu, decrease CTR1
o DMT1
1. Less extent
2. Compete with other divalent



o

In cell: once absorbed bind to MT (blue) and copper chaperones (pink) transport out to
blood via ATP7 (A/B) (yellow)
 This CC (COX17, ATOX1) has 2 roles
o Reduce free Cu+ toxicity to the cell
1. Prevent Cu+ bind to cells for bad interaction
o Transportation
1. COX17-Cu
 Brought to mitochondria
2. ATOX1-Cu
 Brought to organelle
 Facilitate Cu transport to blood
If too much Cu 
 CTR1 reduce
 ATP7 increase
Factor:
 Enhancer
 Amino acid
 Glutathione
 Organic acid
 Inhibitor
 Alkaline
o H2 receptor blocker
o Proton pump blocker
 Phytic acid
 Zn
o Zn stimulate metallothionein syn in intestinal cells
o
Intestinal cell Cu use
o Stored
 Bind to metallothionein
o Used functionally
o Transport through cytosol to blood


Via active transport
 ATPase ATP7A
o Mutation leads to Menke’s disease
Transportation in blood
o Transporter:
 In portal blood
 Albumin
 Transcuprein
 In other blood
 Ceruloplasmin (most active Cu transporter)
o It is also the transporter of Fe
o Made from liver
o Deliver to:
 Liver 1st
 Cu + apoceruloplasmin  Ceruloplasmin (transport protein & enzyme activity)
o Transport Cu to the rest of body
1. `Bind up to 6 Cu+
o Enzyme activity:
1. As a Ferroxidase
 Release Fe from liver storage to transferrin in plasma 
transport Fe to plasma
o Convert ferrous  ferric
o Ferric + apotransferrin  transferrin  transport to
reticulocyte for hemoglobin synthesis

2. SOD (superoxide dismutase)
 Antioxidant
 Cu & Zn depdendent enzyme
 Convert superoxide radical  O2 & H2O2
o H2O2 also toxic to cell
o Need another enzyme to neutralize it  Selenium


Excretion:
o Main site:
 Feces
 Not absorbed in intestine  feces
 Unused Cu from liver  bile  intestine  feces
o Urine
o Skin
o Hair
Function

Regulation of gene expression
o MT metallothionein transcription
o

Regulated by both Cu & Zn
 MT can only be syn in the presence of both  induce gene expression
 Can also expressed by mercury & cadmium  non-essential  to reduce toxicity
 Zn more influence
Imp component of mitochondrial respiratory enzyme
o cytochrome C oxidase
 imp in energy production
 fucntion in the terminal oxidative step in mitochrondrial elextron transport
o Is also Cofactor of dif enzymes
o
o
Interaction with other nutrients:

Fe
o
Imp for normal Fe metabolism
 Ferroxidase activity of hephaestin in enterocyte (Cu-dependent protein)
 Ceruloplasmin
 Responsible for the oxidation of Fe to Fe3+  only then can be bound to transport
protein transferrin for delivery to tissue
 Cu deficiency
 Fe-trapped  secondary -Fe deficiency anemia
Deficiency (premature infant/ genetic disorder)




All enzyme activity affected
Prominent clinical features:
o Related to blood
 Anemia (Fe-resistance)
 Poor wound healing
o Related to collagen & elastin production
 Affected site:
 Blood vessels & heart
 Bones & muscles to the bone
o Related to antioxidant (SOD)
 Not so imp  body has many other  can compensate
Rare cases due to food intake
o Maybe due to too high Zn intake
Other factor:
o Can happen during pregnancy  premature fetus
 Consequence:
 Premature infant
 Why?
 Mother Cu not enough to give to fetus
 During late stage of pregnancy  Cu can be accumulated in fetus liver  large store
for usage when he’s born
 Symptom:
 Failure to thirve
 Fe resistant anemia
 Twisted kinky hair
 Skeletal changes (failure for syn of connective tissue due to collagen & elastin
affected)
o Fractures
o Osteoporosis
o Weakness
o Joint pian
o Abnormal blood vessels
o 2 Genetic disorders:  abnormal Cu lvl in body
 Menkes syndrome (ATP7A)  Cu decrease
 Faulty Cu absorption
o Enterocyte absorb Cu but X release into circulation
o Less severe
o Treatable:
1. Intravenous Cu
 Faulty transport to brain
o Premature death due to Cu deficiency in brain
o More serious  hardly treatable
 Wilson’s disease (ATP7B)  Cu accumulation
 Impaired incorporation of Cu into ceruloplasmin
o But this protein is responsible for Cu to be transport out of liver
o Also accumulate in other part of body : eye, brain
o Toxic  lead to death



Decreased biliary excretion of Cu
Feature:
o Kayser-Fleischer ring in the eyeblack
Treatment:
o Limit absorption of Cu with Cu-binder
1. Bind to Cu in body to reduce free Cu toxicity

Toxicity:



Too much Cu can induce body mechanism to reduce absorption but still got chance to toxic
Cause:
o Deliberate ingestion of Cu salt
o Drinking contaminated water
Symptom:
o Actue toxicity nausea, vomit, diarrhea  fatal
o Chronic Cu poisoning  liver cirrhosis
 Due to contaminated by
 Cu water pipe
 Cooking utensils
 More vulnerable to
 Infant
 Young children
Selenium





Similar chemistry to sulfur
Trace amt needed for cellular function
very toxic in even small doses
o but have a better excretory pathways than Fe & Cu  urine
Can be seen as an ingredient in
o Multivitamins
o Dietary supplements
o Infant formula
A component of antioxidant enzyme (GPx)
o Neutralize H2O2 produced by SOD (Cu antioxidant )
Food source






the selenium content of plant foods and products is extremely variable.
o Depend on the soil Se conc
Whole grain
Seafood
Organ meat
o Tissue esp skeletal muscle can store more Se  meat source
Risk of deficiency;
o Vegan
Form:
o Organic
 Selenomethionine
 Selenocysteine
o Inorganic
 Selenide
 Selenite
 Slelenate

Requirement

Increase for
o pregnancy:
 Se def  miscarriage & CNS defect of fetus
o Lactation
 Breast milk is a source of Se for baby
o Male > female:
 Se def  infertility
 sperm quality
 sperm number
o
Metabolism


Absorption very efficient  blood
o Most ingested is absorbed
o Site: SI
o Most of Se in body found in blood
2 fades:
o Used in selenoprotein enzyme
o Stored in kidney/ liver as SeMet
o Excreted from body
 Urine (primary route)
 Feces (predominant if due to low intestinal absorption)
 Sweat





Different form of Se: (similar absorption rate)
o Organic selenium
 Se compete with sulfur in some AA to form Sec, SeMet
 2 types:
 Selenomethionine
o Mainly found in plant protein
 Selenocysteine
o Mainly in animal protein
 Enter enterocyte via amino acid transport system
 B0AT1
o Na+ dependent neutral amino acid transporter
 rBAT
o neutral & basic amino acid transport protein
o Inorganic Se: (selenium salt)
 Types:
 Selenate
 Selenite
o Less absorption rates
 Absorbed by active sodium-dependent transport
 solute carrier 26 (SLC26)
Hence, no need to convert inorganic   organic
o That’s why Se absorption very efficient
Transport in blood
o Selenoamino acid
 travel free to liver and other tissue
o Selenite
 Reduced by glutathione & glutathione reductase  selenide
 Transport form
 Binds to VLDL or LDL
 Bind to albumin
To liver
o Major organ metabolizes Se
o 2 forms reached liver:
 Se-albumin
 SeMet bound to albumin
o

o
o



2 fades:
1. Incorporated in some protein such as albumin
2. Convert to Sec via transsulfuration pathway
Intact form:
 Sec
 Selenate & Selenite
HSe Converted Sec + dietary Sec—(SCLY selenocysteine bete-lyase)  HSe Selenite – (TRXR / glutathione-glutaredoxin pathway)  HSeSe-Phosphate (final form)
 HSe- --(SPS2) Se-P
 Useful to
 form Sec tRNA  for selenoprotein production
 Transport Se through blood to other tissue by LDL / VLDL
Factor affecting Se absorption:
o Methionine & Cysteine  similar structure to Sec & SeMet
o ADE vitamin  increase Se absorption
Found in:
o RBC
o Liver
o Spleen
o Muscle
o
o
o
Nails
Hair
Tooth enamel
Function
1. Se is essential element for Selenoprotein
o
o
Syn of selenoprotein:
 Sulfur-containing AA + Se  Secysteine
 Selenophosphate  help donate the Selenium to form Secysteine
 Catalyzed by selenophosphate synthetase
o Cofactor= Vit B6
 Se bond with Sulfur in the cysteine /methionine using their SH grp  from there
incorporated into selenoprotein
glutathione peroxidase (GPx)
 Most well known selenoprotein
 Catalyze the reduction of …
 2 peroxides  water & oxidized glutathione (GSSG)
o H2O2
o Organic peroxides (fatty acid peroxides)
 With glutathione (GSH) presence
o Furnish the reducing equivalents in the reaction
o


GSH 把 H2O2 的 oxygen 拿走
** this reduction can be performed by other antioxidant as well:
o Such as:
1. Catalase
2. Peroxidase
o If we lack of one, wont have too severe consequence for short term
o If long term  antioxidant system too saturated  not enough antioxidant
to neutralize ROS  damage body cells
Essential enzyme to maintain the redox state of membrane & cell content
 Esp RBC
o No mitochondria (a imp organelle to maintain optimal redox state)
o Imp to regulate redox state for gas exchange by hemoglobin
o During exchange, peroxide may formed  need GPx to suppress its
formation


o
The activity of GPx  sensitive indicator of Se status
 Less active in deficiency ppl
 4 isozymes
 GPx1 & GPx4 most common in most tissue
o GPx1
1. Rbc
2. Kidney
3. Liver
o GPX4
1. Testes  protec thte testes function
 GPX2
o GI tract
 GPX3
o Kidney
o Lung
o Heart
o Breast
o placenta
 36% OF TOTAL body Se  associated with GPx (Se is always linked to GPx )
Other selenoprotein other than GPX

2. Thyroid Hormone synthesis:

Iodothyronine 5’- Deiodinases

removal of iodine from T4  T3 (active form)
o Se deficiency
 Increase T4
 Decrease T3
3. Keep the stability of membrane
o
o
Membranes are made of UFA  easily oxidized
Need antioxidant system to reduce it
 GPX and other antioxidant like Vit E , SOD, catalase…
 Though there is overlapping function of GPX and Vit E, but they both are needed to run the
job
Deficiency:




Develop in
o premature infants
o person with long time Se-free enteral/parenteral solutions
symptom:
o decline GPX activity in a variety of cell types
o fragile RBC
 membrane not stable
o enlarged heart
o cardiomyopathy
o growth retardation
o cataract formation
o abnormal placenta retention
o deficient spermatogenesis
 GPX4 in testes
o Skeletal muscle degeneration
Impaired thyroid hormone activity
o Selenoprotein  iodothyronine deiodinase  convert T4  T3 (most active thyroid hormone)
Keshan disease
o Degenerative changes in the heart muscle
o Due to mutation of virus in the absent of Se
o Happen in china
Measurement:


Activity of GPX
Blood selenium not informative
Toxicity



Intake in excess of 400ug/d = UL
Acute poisoning
o 1st: GI effects
 Nausea
 Vomiting
 Diarrhea
o Hypersalivation
o Garlic-smelling breath
o hair loss, restlessness, tachycardia, fatigue
Chronic poisoning = selenosis
o
o
o

Nail, hair changes  brittleness & loss
Skin lesion
Neurological effects
 Numbness
 Pain
 Paralysis
Interfere other trace mineral homeostasis:
o Reduce Zn absorption
o Reduce Fe tissue store
o Increase Cu in heart, liver, kidney
o *** there is a complex relationship between all minerals
 Any increment or decrease of any mineral will affect one another
Iodine


The heaviest element commonly needed by living organism
Imp for endocrine system (thyroid hormone)
Food source
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Natural sources of I
o Marine organism
o Plant grown on I-rich soil
Iodized salt
o This is due to Iodine deficiency frequent happen in certain area due to geographical factor  hardly
access to marine food
Absorption is reduced in food with goitrogen (phytochemical)甲状腺激素
o
o
o
Brassica vege (cabbage, broccoli, swede, brussels sprouts)
Maize
Goitrogen
 interfere
 Fe absorption
 ** vegan susceptible to iodine deficiency
 Inactivated by cooking
Requirement
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Increase in pregnant females (10-20%)
o Thyroid hormone increases during pregnant
Increase in lactation
o Iodine source for infant
Metabolism
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Form:
o Iodine convert to  iodide ion (I-)  absorbed
In blood
o Circulate in blood to all the tissue in free IDistribution
o 80% in thyroid gland
 For T4 (thyroxine) synthesis
o Salivary gland
o Gastric mucosa
o
o

Choroid plexus
Lactating mammary gland
Synthesis of thyroxine
o When body need thyroid hormone  increase TSH (thyroid-stimulating hormone)  stimulate
tyrosine-rich thyroglobulin (a protein made by follicular cells of thyroid gland)  main structure of
thyroid hormone  make available for iodination
 Thyroglobulin is made of
 Tyrosine (NE amino acid made form melanin)
 iodine
o In the meanwhile, I- is pumped actively into the thyroid follicular lumen
o Iodination:
 Thyroglobulin + iodine -- (iodide peroxidase)  monoiodothyronine  diiodothyronine 
triiodothyronine (T3)  thyroxine(T4)

o
o
o
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Thyroid gland produced ratio of thyroid hormone:
o 90% T4 (T2 *2)
o 10% T3 (T2 + T1)
T4 transport
 Released from follicles to blood  transport by “thyroid-binding protein”  to all cells of
body
At target cell:
 Deiodination of T4
 T4 – (deiodinase <Se-containing enzyme>)  T3 (most active thyroid hormone) +
iodine
The consequence of The released iodine
  conserved and sent back to thyroid gland

 unused  lost in urine or feces
o
Function:
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
Thyroid hormone
o Maintain metabolic rate by
 Control energy production
 O2 consumption in cells
o Normal growth & development
Normal protein metabolism in brain & CNS
o For fetus & neonate
o Needs Iodine
o ** that’s why pregnant & lactating mom needs more Iodine
Deficiency
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Goiter
o
o
o
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Can happen in both hypo & hyperthyroidism 不可以断定大颈包是 hypo/ hyper
Enlarged thyroid gland
Due to hypertrophic, hyperplasic change in gland’s follicular epithelium
 Lack of thyroid hormone  pituitary gland produce mre TSH to increase production 
increase stimulation of the epithelial cells  but still cant increase syn thyroxine vicious
cycle  excess stimulation hypertrophy
 Cell enlarged due to lack of iodine to complete thyroxine synthetic process
Hypothyroidism
o Due to
 Iodine deficiency
 Or selenium deficiency even in iodine efficient
 Cannot produce the active thyroid hormone T3
o Characteristic: (low metabolism)
 Weight gain
 Lethargy
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Poor cold tolerance
Bradycardia

Myxoedema 粘液性水肿
Dif age dif consequence:
o Pregnant iodine-deficiency  developing embryo/ fetus
 Suffer neurological deficit
 Lose their pregnancies
 Fetus fail to develop and dies in utero
o Children / infant
 Consume iodine deficient diet
 Fail to grow normally
 Low development of intellectual
Common case:
o Eat little iodine + diet rich in Brassica vege
Toxicity
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Hyperthyroidism
Toxic modular goiter
o Due to excess secretion of T3 & T4
o But the symptom is very dif to hypo-goiter
 Like bulging eyes
 Weight loss
To test for hyper/hypo:
o Look for TSH! Very sensitive indicator
 Hypo
 Increased
o Our body not enough TH
 Hyper
 Absent/ decreased
o As our body has more than enough of TH

T6- Alcohol
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
The one that can be consumed = ethanol (2 c  C2H5OH)
o Ethanol= ethyl alcohol
o Mostly produced by fermentation of glucose in plant
 Vegetarian friendly
Labeling law:
o Needed to indicate % alcohol by volume (abv) in all alcoholic drink
 10% abv= 7.9g alcohol/100mL
Nutritional value:
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
7kcal (29kJ)/ g
May contain other nutrient since is obtained from plant
o But small amt only  X depend on alcohol to get these nutrient
 Propyl alcohol
 K

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Riboflavin
Niacin
Recommendation Intake:
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Dif type of alcoholic drink  if intake size
o As we need to look at the ethanol conc
Men: 3-4 unit/d
Women: 2-3unit/d
2d/week should be alcohol free
Pregnant: not more than 2-4 unit/week
o Excessive alcohol consumption during pregnancy fecal alcohol syndromes
 Cause facial deformities & growth prob
 Short nose
 Thin upper lip

o
Indistinct philtrum 人中 (easiest to identify)
 Flat midface
 Short palpebral fissure
 Alcohol causes higher blood alcohol concentrations in your developing baby than in your
body because a fetus metabolizes alcohol slower than an adult does. Alcohol interferes with
the delivery of oxygen and optimal nutrition to your developing baby.
If too much  fecal die
o
Metabolism:
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Absorbed in stomach & jejunum distribute throughout body water including blood  distribute mainly to
brain & liver
Ethanol is readily absorbed through the entire gastrointestinal tract. It is transported unaltered in the
bloodstream and then oxidatively degraded in tissues, primarily the liver, first to acetaldehyde and then to
acetate.
In tissues other than the liver, as well as in the liver itself, the acetate subsequently is converted to acetylCoA and oxidized via the TCA cycle.
At least three enzyme systems are capable of ethanol oxidation:
o alcohol dehydrogenase (ADH)
o the microsomal ethanol oxidizing system (MEOS; also known as the cytochrome P-450 system)
o catalase, in the presence of hydrogen peroxide
Of these, the catalase-H2O2 system is the least active, probably accounting for <2% of in vivo ethanol
oxidation.
Alcohol dehydrogenase (ADH) acetaldehyde
o Then broken down again Aldehyde dehydrogenase (ALDH)  acetate
o These 2 enzyme is mainly found in liver
o
o
o
o
o
o

Average  5-10g is metabolized per hour
 Some excreted in breath  monitor alcohol intoxication
Ethanol  acetaldehyde  toxin that get you drunk
 In liver, further detoxify by ALDH  acetic acid  excrete in urine
 So that you may not be drunk anymore
Require NAD+
 Depletes NAD+  force shit to microsomal system that X need NAD+ = MEOS
Also expressed in GIT
 But significantly different in gender
 Female lesser ADH in GIT 
o Young premenopausal femal develop higher blood alcohol than male with
equal consumption  lower tolerance of alcohol and greater risk of toxic
effect in liver
Affect other metabolism
 NAD+ are needed for other reaction  the increase ratio of NADH:NAD+  impair
 TCA cyc;e
 Gluconeogenesis
 Fatty acid oxidation
o
Microsomal ethanol-oxidizing system (MEOS)
o Inducible by ethanol  to increase efficiency of hepatocyte to metabolize alcohol
o A system of alcohol metabolism induced by alcoholics
 CYP2E1 enzyme  help ADH to metabolize ethanol to acetaldehyde
 The amt of ethanol is too much  need another enzyme to help ADH
 Mostly in liver
o Effect on other metabolism
 It can also accelerate the metabolism of other sub etabolized by microsomal system 
increase their tolerance as well
 Fatty acid
 Aromatic hydrocarbons


 Steroids
 Barbiturate drugs
Catalase: (not included in MEOS)
o Help ADH to convert to acetaldehyde
o Mostly found in brain
 To reduce the hangover symptom
Other factors:
o Food in stomach can slow alcohol absorption
o Smaller ppl have smaller liver  metabolize alcohol slower
 Women has smaller liver than men  intoxicate faster
o The build up of acetaldehyde leads to headache, nausea & vomit
Fatty liver:

Impair fatty acid oxidation due to reduce NAD+
o Build up of acetyl-CoA in liver
 Encourage liver synthesis FA with time lead to TAG accumulation in liver
Toxicity
Acetaldehyde toxicity
 Able to attach covalently to proteins  protein adduct
o If adduct an enzyme  impair the enzyme activity
 Impede formation of microtubules in liver cell
o Cuase development of perivenular fibrosis  initiate cirrhosis
High NADH:NAD+ ratio
 Metabolic shift to hydrogenation
o Account for fatty liver
 Trhough anabolic activity producing fatty acicds
o Lactic acidemia
 High blood lactate level
 Increase reduction of pyruvate to lactic acid




Slow down hydrogenase reaction of TCA cycle
o Accumulation of citrate which positively regulate acetyl-CoA carboxylase
 Enzyme convert acetyl-CoA  malonyl CoA by attaching a carboxyl grp
 A key regulatory enzyme for synthesis of FA from acetyl0CoA
 Hence, direct metabolism away from TCA cycle oxidation  fatty acid synthesis
The effect of NADH on glycerophosphate dehydrogenanse reaction (GPDH)
o Favor reduction of DHAP to glycerol-3-phoshpate if NADH conc is high
 Provide glycerol component in the synthesis of TAG
impair gluconeogenesis
o Affect glutamate dehydrogenase GluDH reaction
o Imp in conversion of Amino acid to their carbon skeleton by transamination & release amino group
o
o

A shift of glutamate and deplete alpha-ketoglutarate which is a major acceptor of amino grp in the
transamination of amino acid
Several stages : depend on how much alcohol in our blood


o
Common effect:
o Heart beat fast
o Facial Flushing:
 Vasodilation
o Anesthetic:
 CNS depressant
o Diuresis:
 Alcohol act on pituitary gland  may lead to dehydration
The reactive metabolite led to toxicity: acetaldehyde:
o Acute toxicity:
 Target: CNS suppression
 Can be seen very fast
 Sedative & hypnotic effect, cognitive impairment, motor incoordincation,
hallucinogenic, euphoriant effect, learning, memory deficit
o Chronic toxicity:
 Target: Liver damage
 Accumulation of fat
o Complex mechanism
 Oxidative stress, inflammation, necrosis in liver, liver failure, cancer
o Teratogenicity:
 Birth defect
o
Thiamine deficiency


2 reason
o Ethanol reduces thiamine intake & absorption
o Increase needed for ethanol metabolism
 Thiamine needed for GSH production  antioxidant needed for ethanol metabolism

Consequence:
o Wernicke’s encephalopathy
o Korsakoff’s psychosis
Genetic polymorphisms in alcohol metabolism:


East Asian & American Indian
o Higher efficiency of ADH
 Can breakdown ethanol to acetaldehyde faster
East Asian: ALDH 2*2
o Less efficient than ALDH2
 ALDH2 is the enzyme normally break down acetaldehyde
 Hence lead to  Asian flush syndrome/Asian glow
 Bcs produce AA very fast  that make us drunk
 AA unable to detoxify efficiently by ALDH2*2 to acetic acid
 Hence get drunk easily
Benefit:


Light – moderate consumption of alcohol reduce risk of CHD in men & post-menopausal women
mechanism
o increase HDL
 prevent obstruction of blood vessel in heart
o polyphenolic comp in wine
 resveratrol
 reduce plasma LDL
Paracetamol & alcohol


chronic alcoholics are at increased risk of paracetamol hepatotoxicity not only following overdose but also
its therapeutic use
o in chronic alcoholics, CYP2E1 increase
o paracetamol will produce toxic damaging liver
the paracetamol toxicity is more severe in CYP2E1 increased ppl  risk of hepatotoxicity
o induction of CYP2E1 by ethanol increases formation of toxic metabolite of paracetamol